Conditions: Malignant Glioma
Keywords: Glioblastoma Glioma PVSRIPO Duke Pro00077024 Brain tumor Istari Recurrent GBM rGBM
Allocation: RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 121
Healthy volunteers: no

Brief summary:
This is a phase 2 study of lerapolturev, an oncolytic polio/rhinovirus recombinant, in adult patients with recurrent World Health Organization (WHO) grade IV malignant glioma.

Detailed description:
This is a Phase 2 study of lerapolturev, an oncolytic polio/rhinovirus recombinant, in adult patients with recurrent World Health Organization (WHO) grade IV malignant glioma. The objective of this study is to investigate the safety and efficacy (anti-tumor response and survival) of lerapolturev in recurrent WHO grade IV malignant glioma.

Patients will be administered lerapolturev intratumorally via convection-enhanced delivery (CED) using an intracerebral catheter placed within the enhancing portion of the tumor. Retreatment with lerapolturev is allowed, provided retreatment eligibility criteria are met.

Arms:
arm 1: lerapolturev administered once intratumorally by convection-enhanced delivery arm 2: lerapolturev administered once intratumorally by convection-enhanced delivery plus one dose of lomustine at 8 weeks post-lerapolturev dosing

Interventions: intervention 1: lerapolturev intervention 2: Lomustine
Intervention descriptions: intervention 1: A single dose of lerapolturev, an oncolytic polio/rhinovirus recombinant intervention 2: one cycle of oral lomustine

Protocol document:
Prot_000.pdf: 
A Multicenter Phase 2 Study of Oncolytic 
Polio/Rhinovirus Recombinant (PVSRIPO) in 
Recurrent WHO Grade IV Malignant Glioma Patients
Protocol Number: Pro00077024 (Multicenter) 
Version Date: 07 February 2020 
Overall Study Principal Investigator: 
Dina Randazzo, DO, Duke University Medical Center 
Protocol Version: 08 
Sponsor: 
Istari Oncology Inc. 
6 Davis Drive 
Durham, NC 27709 
IND #: 14,735 
Signature(s): 
____________________________________________ 
07 February 2020 
Henry Friedman, MD, Chief Medical Officer, Istari   
Date: 
Oncology, Inc. 


Pro00077024: PVSRIPO 
 
 
 
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Page 2 of 94 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NOTICE: 
DUE TO KNOWN PVSRIPO-MEDIATED TREATMENT EFFECTS, INCREASED 
TUMOR SIZE ON RADIOGRAPHIC IMAGING FOLLOWING PVSRIPO 
ADMINISTRATION MAY OCCUR. EXCEPT IN CASES OF EMINENT LIFE-
THREATENING EMERGENCY, CONSULT WITH STUDY-DESIGNATED NEURO-
ONCOLOGIST(S)/INVESTIGATOR STEERING COMMITTEE PRIOR TO 
INITIATING NON-PROTOCOL-SPECIFIED TUMOR TREATMENTS OR 
PERFORMING SURGICAL RESECTION.  
Per-Protocol management of cerebral edema/ pseudoprogressive/ polycystic/ 
expansive tumor appearance 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 Initiation of low dose steroids (dexamethasone ≤ 4mg/day) if rapid 
administration is required  
o Preferred: Low dose bevacizumab (7.5mg/kg q 3 weeks; few cycles as 
possible to achieve symptom control) 
o Other supportive care treatments, as required (eg, antiepileptics)  
• PVSRIPO’s immune-mediated mechanism of action (MOA) is known to result in 
atypical tumor imaging responses that can manifest as polycystic 
pseudoprogressive tumor enlargement 
• Due to PVRIPO’s MOA, reliance on radiographic imaging standards (iRANO, etc.) 
for determining disease progression is not valid 
• Time to objective radiographic anti-tumor response ranges from approximately 5 
to 29 months post-infusion in the Phase 1 study (median time to response 15 
months) 
• In order for patients to have the best opportunity for anti-tumor response, 
experience suggests that patients should be managed as noted above 


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Summary of Protocol Amendment Changes 
Version Dates 
Summary of Major Changes by Section 
27FEB2019 to 
07FEB2020 
•
This version replaces/supersedes a version of the amendment dated 30JAN2020, 
which contained a typographical error on page 61 and was circulated inadvertently. 
No patients were treated under the version circulated 30JAN2020
•
Throughout protocol: Primary Endpoints changed to Objective Radiographic 
Response and Duration of Response, while Overall and Landmark survival were 
changed to secondary endpoints. Disease Control Rate also added as a secondary 
endpoint. Exploratory endpoints updated to include description of anti-tumor 
responses following PVSRIPO retreatment and based on level of institutional 
experience using PVSRIPO.
•
Throughout protocol: Noted requirement for Investigators to consult with study-
designated neurooncologist and/or Investigator Steering Committee (ISC) prior to 
removing a patient from study and/or use of non-protocol-specified therapies.
•
Throughout protocol: clarification that catheter placement procedure is not required to 
be performed under general anesthesia.
•
Throughout protocol: updated treatment-related adverse event collection to include 
non-standard of care screening procedures required for PVSRIPO infusion.
•
Section 5: Added a tabular protocol synopsis.
•
Section 5: New sites are no longer required to wait 2 weeks between each of the first 
3 patients infused; hold only after the 1st subject infused after Sponsor approval to 
proceed to next.
•
Section 5 and 11.1 (Inclusion Criterion 1a) and Section 9.1.1: language regarding 
catheter tip placement updated to allow for placement within, or as close to, 
enhancing disease as possible while remaining at least 1 cm from the ventricles.
•
Section 5 and 11.2 (Exclusion Criterion 3f) and Section 9.1.6: History of any 
gadolinium allergy changed to history of anaphylactic reaction to gadolinium.
•
Section 5 and 11.2 (Exclusion Criterion 9): Clarified requirements for prior receipt of 
standard of care therapies.
•
Section 5 and 11.2: Added back Exclusion Criterion 16, which excluded patients 
enrolled prior to Amendment 7 who have history of hypersensitivity to lomustine, 
dacarbazine, or any of its excipients.
•
Section 9.1.3 and Table 1: Removed Magnevist® from PVSRIPO infusate, as well as 
removal of MRI 4 hours post-infusion to infusate visualization.
•
Section 9.1.6 Safety Considerations: Under Special Considerations, added note that it 
is recommended to not start bevacizumab use within 4 weeks of PVSRIPO infusion
(per bevacizumab prescribing instructions); however earlier use at physician 
discretion, and if in line with Institutional use guidelines following biopsy was 
permitted.
•
Added Section 9.2 to allow and provide eligibility criteria for PVSRIPO retreatment in 
patients ≥ 12 months out from prior PVSRIPO infusion. Note: the balance of the 
protocol was also updated to account for PVSRIPO retreatment, including addition of 
PVSRIPO Retreatment Study Tests and Procedures (Table 2), located in Section 5.
•
Section 10.1.4: Updated to reflect current product handling, preparation, and 
dispensing recommendations.
•
Section 11.2: Inclusion/Exclusion Notes: Updated multifocal disease stabilization to 
equal no size increase >0.5cm in any direction on 2 consecutive MRI at least 3 
months apart
•
Section 12.1 and Table 2: For PVSRIPO retreatment only, the acceptable maximum 
time of polio vaccination booster is 6 months prior to infusion.
•
Section 12.3, Section 12.7.5 and Table 1: updated to reflect removal of timepoints for 
collection of biomarkers.
•
Section 12.7.3: Updated to clarify current radiographic review practices.
•
Section 12.8.4: Serious Adverse Event (SAE) Reporting procedures (particularly 
procedures related cerebral edema) were updated to reflect current Sponsor policies.
•
Section 14 – Statistical Methods and Data Analysis: Updated to reflect the statistical 
approach based on changes to primary and secondary endpoints.


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Section 14.2: Added clarification regarding possible use of additional relevant data 
sources to bolster the historical control comparison. 
02NOV2018 TO 
27FEB2019 
•
Added overall study PI, Dina Randazzo, DO, DUMC.
•
Throughout protocol: Removed treatment arm randomizing 50% of patients to receive 
a single dose of lomustine 8 weeks after PVSRIPO infusion given an interim review 
noting no decrease in potential prognostic indicators of long-term survival (eg, dose 
and duration of use of corticosteroids or bevacizumab) with addition of a single dose 
of lomustine, but increased hematological toxicities associated with lomustine use; 
added additional safety information. Endpoints and objectives have been modified 
accordingly, throughout. Data will still be summarized by treatment arm for the 
patients randomized to and receiving lomustine at week 8 post PVSRIPO infusion, 
relative to PVSRIPO alone.
•
Section 7.3 Study Purpose/Rationale: Updated that survival up to +81 months has 
been noted in Phase 1 study with PVSRIPO.
•
Section 11.1 Inclusion Criteria: Clarified inclusion criterion 1 with regard to site 
neurosurgical confirmation requirement that biopsy at time of catheter placement and 
catheter placement ≥ 1 cm from ventricle can be completed safety within protocol 
requirements, in addition to sponsor designated reviewer requirements regarding 
confirmation of patient meeting tumor size and location requirements.
•
Section 11.2 Exclusion Criteria: Removed EC 16 referring Patients with a known 
history of hypersensitivity to lomustine, dacarbazine, or any components of lomustine.
•
Table 1 (footnote i) and Section 12.2, Day 0 (after the infusion): Clarified that the post-
PVSRIPO infusion MRI (without contrast) should occur as quickly as possible after 
the completion of the infusion to track the infusate; ideally, this post-infusion MRI 
should be obtained within 2h of completion of infusion but within 4h maximum is 
allowed, given scheduling constraints.
•
Table 1 (footnote c) and Section 12.3 Clarified that the items required for the PE must 
be documented/completed within 24h (±4h) of discharge.
•
Table 1 (footnote c) and Section 12.3 Clarified that the items required for the PE must 
be documented/completed within 24h (±4h) of discharge.
•
Table 1 and Section 12.3 Removed Week 12 visit and blood draw for immunologic 
analysis that was associated with lomustine use.
•
Section 12.4: Follow-Up for Off-Study Patients/Patients requiring retreatment with 
PVSRIPO: Added that for patients who initially benefitted from PVSRIPO, are at least 
12 months post-infusion on this study who experience a recurrence and their clinician 
feels they may benefit from an additional infusion of PVSRIPO, they may be 
considered for a separate but related long-term follow-up rollover/re-treatment 
protocol.
01JUN2018 to 
02NOV2018 
•
Sections 6 Study Schema, 9.1 Investigational Plan, 9.1.8 Randomization, 14.10
Sample Size Calculations: Prior to the activation of additional centers in the
multicenter study and compilation of other center historical control data, to date
(October 2018), DUMC has enrolled 48 subjects on the single center phase 2 study.
As such, enrollment is being increased slightly (up to 40 additional patients; from N=62
to up to 102, distributed evenly across the study arms) in an interim fashion to allow
time for continued enrollment during other site historical control data compilation,
corresponding sample size calculations/adjustments and possibly additional FDA
discussions.  As stated previously, sample size/statistical power will be updated if
necessary via a future amendment once the historical control data from other centers
are available and analyzed.
•
Sections 9.1.4.1 Study Related Biopsy, 9.1.4.2 Archival Tissue and 9.1.4.3 Future
Surgical Procedures: Clarified that only the tests outlined in the pathology manual
would be sent to DUMC for analysis.
•
Section 14.9 Interim Analysis: Changed timing of interim analysis to occur from when
16 patients in each arm reached 6 months post-infusion to when 16 patients in each
arm from the other institutions collectively reached 6 months post-infusion, in addition
to when 16 patients in each arm reached this milestone at DUMC. Removed changes
in immune measures (Tregs) as an interim analysis endpoint given that very few
samples from the Phase 1 study have been analyzed, to date. Clarified that the interim
analysis focusing on feasibility of PVSRIPO at other institutions will be based primarily
on safety endpoints given that the analysis is to take place 6 months after PVSRIPO
infusion, prior to when separation in survival curves occurred relative to historical


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control patients in the Phase 1 study. However, early bevacizumab use as a potential 
surrogate marker of long term survival as outlined, will also be investigated at other 
centers and DUMC. Additional details will be outlined in the statistical analysis plan 
and finalized prior to conducting the interim analysis. 
•
Section 10.2 Study Agent Lomustine: In keeping with the memo to file dated 
17AUG2018, the 5 mg dose of lomustine was discontinued by the manufacturer and 
as such, reference to the 5mg dose was deleted and the text was amended to state 
that the single dose of lomustine to be given at week 8 should not exceed but be 
within 10mg (the new lowest dose level capsule) of 110 mg/m2 or 90 mg/m2 if on 
bevacizumab since PVSRIPO infusion.
•
Section 11.2 Exclusion Criteria: Clarified in this quoted section of exclusion criterion 
#8: “Patients may not be less than 12 weeks from radiation therapy…” that this 
specifically refers to radiotherapy of the brain; it now reads: “8. Patients may not be 
less than 12 weeks from radiation therapy of the brain, unless progressive disease 
outside of the radiation field or 2 progressive scans at least 4 weeks apart or 
histopathologic confirmation”. Given recent inquires, for EC 15, added a note on how 
to clarify if a patient has an unrelated malignancy requiring current active treatment by 
stating that if patient required treated for unrelated malignancy other than exceptions 
noted within the past 3 years, a letter from their treating oncologist for the unrelated 
malignancy must be on file confirming that said unrelated malignancy does not 
require current active treatment (prophylactic like tamoxifen OK) and that the patient is 
stable with low risk of recurrence and/or death within the next 3 years (ie, is stable). If 
this letter is not on file, a consult with the Sponsor’s medical designee is required prior 
to submitting the patient for enrollment in the trial.
•
Table 1and Section 12.3 Follow-up PVSRIPO Infusion: Added 3 ml of blood collection 
at Day 1 (or Day 2) post-PVSRIPO infusion to explore inflammation-associated 
biomarkers/for immunologic analysis.
•
Section 12.8.6 Definition of Unacceptable Adverse Event: In response to a site 
question, clarified language regarding unacceptable AE to specify relationship to 
protocol/test procedure, listed the tests/procedures that were applicable and defined 
what reversible means; an unacceptable AE is any grade 3 or grade 4 toxicity 
considered related (possibly, probably or definitely) to a protocol treatment (includes 
surgical biopsy/infusion procedure, PVSRIPO, lomustine, bevacizumab, 
corticosteroids) that is not reversible (ie, does not improve to ≤ grade 2 with exception 
of neurologic events, which must only improve from highest grade level to next lower 
grade level) within 2 weeks. This includes any treatment-related life-threatening event 
or any treatment-related death. No material changes were made to the exceptions 
that follow this paragraph.
18OCT2017 
to 
01JUN2018 
•
Section 0 Purpose: Under exploratory objectives, added: Obtain the quantitative gut
microbiome profile via the OMNIgene®•GUT (OMR-200) kit to determine any potential
influence in response to PVSRIPO or PVSRIPO/lomustine and to explore future
molecular genetic analyses of the buffy coat to determine the genetic characteristics of
these samples to determine any potential influence in response to PVSRIPO or
PVSRIPO/lomustine.
•
Section 5.2 Design and Procedure: Added that as an additional precaution, sites who
have never infused PVSRIPO intratumorally via an intracerebral catheter must wait at
least 14 days (± 2 days) between infusing the first 3 subjects enrolled at their site until
confirmation that the procedures have been conducted per protocol has been
confirmed; clarified that infusion of PVSRIPO occurs over approximately 6.5hrs.
•
Section 6 Study Schema: Updated study schema to include overall N and n for each
treatment arm; Section 9.1.1: Updated that a FDA cleared stereotactic guidance
system could be utilized to assist with catheter placement from Brainlab Vector Vision
system.
•
Section 7.2.6 PVSRIPO Clinical Experience: provided updates and clarifications
around the PVSRIPO clinical experience, to date.
•
Section 8 Objectives and Endpoints: added that exploring any potential genetic
influence on response would include the buffy coat; added exploring the quantitative
gut microbiome profile via the OMNIgene®•GUT (OMR-200) kit to determine any
potential influence in response to PVSRIPO or PVSRIPO/lomustine.
•
Section 9.1.2 PVSRIPO Infusion: Clarified that A Medfusion™ 3500 infusion pump
(Smiths Medical, Minneapolis, MN) or any other comparable FDA-cleared syringe


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infusion pump could be utilized for infusion after obtaining approval by the sponsor or 
their designee. Also clarified that for the post-PVSRIPO infusion MRI, no additional 
contrast agent would be given, and that the post-infusion CT was also performed 
without contrast. 
•
Section 9.1.3 Gadolinium Distribution Quantitation: Clarified that the scan following
PVSRIPO infusion would be conducted with no additional contrast agent to track the
distribution of the contrast agent given with the PVSRIPO infusion.
•
Section 9.5 Definition of Evaluable Subjects and On-Study Subjects: Clarified that if
the treating clinician felt adjustments in routine bevacizumab dosing were warranted, a
subject would come off study but that accidental increases in bevacizumab dosing (ie,
single or not routine) would not result in the subject coming off study and that these
occurrences would be reviewed with the site PI.
•
Section 9.1.4.3 Future Surgical Procedures and Section 11.6 Follow Up for off Study
Patients: Added that subjects and next-of-kin would be asked to provide consent to
obtain subject brains for post-mortem examination.
•
Section 9.1.6 Safety Considerations: under Surgical Complications, added standard
risks language associated with routine stopping of anti-coagulation therapy prior to
surgical procedures; clarified that if a subject required planned treatment with
bevacizumab doses > 7.5 mg/kg every 3 weeks, they would be considered off study
and enter the follow-up phase; under Allergic Reactions to Contrast Agents, added
that given new information of possible retention of gadolinium based contrast agents,
only MRIs absolutely necessary for the proper management of a subject’s brain
cancer will be obtained.
•
Section 9.1.8 Randomization: listed the overall study N and n for each of the study
arms, for clarity.
•
Section 10.1.4 Dispensing and Preparation, clarified that thawed vials of PVSRIPO
are stable at 4°C for 48 hours and that PVSRIPO contained in the clinically intended
delivery apparatus (ie, ready for infusion) is stable at room temperature for 18 hours,
but should be used as soon as possible.
•
Section 11.2 Exclusion Criteria (EC): for greater clarity, modified EC number 6 to
specify time restrictions for particular treatments prior to receiving study drug; added
to EC number 10 that tumors with contrast-enhancing tumor component crossing the
midline (crossing the corpus callosum) are also exclusionary; also clarified language
so it is clear that extensive leptomeningeal disease is excluded but tumor touching
leptomeninges is allowed.
•
Section 12 Screening and on-study Tests and Procedures: Table 1and throughout
Section12: added that 4-6ml of whole blood would be collected for isolation of buffy
coat at the screening visit and that a stool sample would be obtained at screening for
a baseline sample (prior to PVSRIPO infusion) and at 8 weeks post-PVSRIPO infusion
for all newly enrolled patients; those already treated with PVSRIPO under a previous
protocol version would not have a baseline sample but would provide a stool sample
for OMNIgene analysis at their Week 8 visit or at their next clinic visit if they have
already passed the Week 8 visit; clarified that the baseline MRI of the brain would be
obtained both with and without gadolinium contrast but that the MRI within 4h of
PVSRIPO infusion and post-infusion CT after catheter removal would be obtained
without contrast; clarified that after week 52 and for subjects in the follow-up period
(off-study), that MRIs should still be obtained per the institution’s SOC and all images
transmitted to the sponsor or their designee at least every 6 months.
•
Section 12.7.4 Laboratory Evaluations: Added that in addition to immunologic testing,
that genetic and gut microbiome testing may be included in the tests described in
Section 14.7.
•
Section 12.8.4 Reporting of SAEs: clarified that SAEs must be reported by the
investigator to the Sponsor within 24 hours of discovery if the event occurs during the
clinical study and within 30 days after subjects are taken off study), whether or not the
SAE is considered to be related to the study drug(s).
•
Section 14.7 Exploratory Objectives: Clarified that the exploratory objective referring to
genetic markers which are predictors of response referred to tumor genetic markers;
added obtaining the quantitative gut microbiome profile via the OMNIgene®•GUT
(OMR-200) kit to determine any potential influence in response to PVSRIPO or
PVSRIPO/lomustine and obtaining the future molecular genetic analyses of the buffy
coat to determine the genetic characteristics of these samples to determine any


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potential influence in response to PVSRIPO or PVSRIPO/lomustine as exploratory 
objectives/analyses; added an exploratory objective as part of a smaller sub-study 
only for patients enrolled at DUMC, to explore inflammation-associated biomarkers, 
immune cell phenotype and innate and adaptive immune competence pre-PV boost, 
post-PV boost and 1 week post-PVSRIPO infusion in subjects randomized at this 
center. All of the changes noted here were also made to other relevant sections/tables 
throughout the protocol (eg, Section 5 (Protocol Synopsis and Research Summary, 
Section 12 (Screening and on-Study Tests and Procedures), Section 8 (Objectives 
and Endpoints), Table 1 Schedule of Study Tests and Procedures).  
•
Section 14.9 Interim Analysis: corrected reference to NDA to BLA, given that
PVSRIPO would be approved under a Biologics License Application.


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Investigator Agreement Page for Pro00077024 (Protocol Version Multicenter 08) 
 
I agree: 
 
• To assume responsibility for the proper conduct of the study at this site. 
• To conduct the study in compliance with this protocol, with any future 
amendments, and with any other study-conduct procedures provided by Istari 
Oncology, Inc. or their designee. 
• Not to implement this protocol, or any deviations from or changes to the protocol, 
without agreement from the Sponsor and prior review and written approval from 
the institutional review board, except where necessary to eliminate an immediate 
hazard to the subjects or to meet administrative requirements of the study (where 
permitted by all applicable regulatory requirements). 
• That I am thoroughly familiar with the appropriate use of the investigational 
product(s), as described in this protocol, and any other information provided by 
the Sponsor, including but not limited to the current investigator’s brochure 
provided by the Sponsor. 
• That I am aware of, and will comply with, good clinical practices and all 
applicable regulatory requirements. 
• To ensure that all persons assisting me with the study are adequately informed 
about their study-related duties and functions as described in the protocol. 
• To periodic on-site monitoring of the electronic case report forms (eCRFs) and 
source documents by Sponsor or designee and to on-site inspection of eCRFs 
and source documents by appropriate regulatory authorities, including but not 
limited to the US Food and Drug Administration, local governing regulatory 
bodies, and institutional review board inspectors. 
• That the subjects to whom the investigational product will be administered will be 
under my personal supervision or under the supervision of an investigator 
responsible to me. 
• That I will not supply the investigational product to any other investigator, or to 
any clinic, for administration to a human being. 
 
 
Investigator Name: ____________________________________________________ 
 
Investigator Signature: _________________________________________________ 
 
Date: ________________________________________________________________ 










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2 
LIST OF TABLES 
Table 1. Schedule of Study Tests and Procedures for initial PVSRIPO Treatment ....... 23 
Table 2. Schedule of Study Tests and Procedures for PVSRIPO Retreatment ............. 26 
Table 3. Accrual of Unacceptable Adverse Events........................................................ 76 
Table 4. Probability of Unacceptable Adverse Events ................................................... 76 
Table 5. Characteristics of the Patients within the Historical Control Group .................. 93 
3 
LIST OF FIGURES 
Figure 1. The genetic structure of PVSRIPO and its precursors. .................................. 33 
Figure 2. Pathways involved in PVSRIPO oncolytic immunotherapy. ........................... 34 
Figure 3. Genetic structure of PVSRIPO ....................................................................... 54 


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4 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
aPTT 
Activated Partial Thromboplastin Time 
CAP 
College of American Pathologists 
CBC 
Complete Blood Count 
CCNU 
Chloroethyl-Cyclohexyl-Nitrosourea (Lomustine) 
CED 
Convection-Enhanced Delivery 
CI 
Confidence Interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Comprehensive Metabolic Panel 
CNS 
Central Nervous System 
CRO 
Clinical Research Organization 
CT 
Computed Tomography 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DOR 
Duration of Response 
DSMB 
Data and Safety Monitoring Board 
DUMC 
Duke University Medical Center 
DVT 
Deep Vein Thrombosis 
EC 
Exclusion Criteria 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EGFR 
Epidermal Growth Factor Receptor 
EGFRvIII 
Epidermal Growth Factor Receptor (variant III) 
eIF 
Eukaryotic Initiation Factor 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in the first second of expiration  
FLAIR 
Fluid-Attenuated Inversion Recovery 
G-CSF 
Granulocyte-Colony-Stimulating Factor 
GBM 
Glioblastoma 
GCP 
Good Clinical Practice 
Gd-DTPA Gadolinium Diethylenetriamine Pentaacetic Acid 
GM-CSF 
Granulocyte-Macrophage Colony-Stimulating Factor 
HCG 
Human Chorionic Gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
HMGB1 
High Mobility Group 1 Box 
HRV2 
Human Rhinovirus Type 2 
HSA 
Human Serum Albumin 
IC 
Inclusion Criteria 
ICF 
Informed Consent Form 
ICH 
International Council of Harmonization 
IEC 
Institutional Ethics Committee 
IgG 
Immunoglobulin G 
IND 
Investigational New Drug 
iRANO  
Immunotherapy Response Assessment in Neuro-Oncology 
IRB 
Institutional Review Board 
IRES 
Internal Ribosomal Entry Site 
ISC 
Investigator Steering Committee 
IV 
Intravenous 
KPS 
Karnofsky Performance Status 
LAR 
Legally Authorized Representative 
LS 
Landmark Survival  
LSQ 
Lymphocyte Subset Quantitation 
MDSC 
Myeloid-Derived Suppressor Cell 


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MGMT 
O6-methylguanine-DNA methyltransferase 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
NDA 
New Drug Application 
NK 
Natural Killer 
NHP 
Non-human Primate 
NSF 
Nephrogenic Systemic Fibrosis 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cell 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed death-ligand 1 
PET 
Positron Emission Tomography 
PI 
Principal Investigator 
PJP 
Pneumocystis jiroveci pneumonia 
PKC 
Protein Kinase C 
PRTBTC 
Preston Robert Tisch Brain Tumor Center 
PT 
Prothrombin Time 
PV 
Poliovirus 
PV1 
Serotype 1 Live-Attenuated (Sabin) PV Vaccine 
PV1S 
Poliovirus Serotype 1 (Sabin) 
PVSRIPO Polio/Rhinovirus Recombinant 
RANO 
Response Assessment in Neuro-Oncology 
SAE 
Serious Adverse Event 
SAM 
Study Administration Manual 
SD 
Standard Deviation 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SIADH 
Syndrome of Inappropriate Antidiuretic Hormone 
SOC 
Standard of Care 
TCID 
Tissue Culture Infectious Dose 
TERT 
Telomerase Reverse Transcriptase 
US 
United States 
WHO 
World Health Organization 
 
 


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5 
PROTOCOL SYNOPSIS AND RESEARCH SUMMARY 
Protocol Title: 
A Multicenter Phase 2 Study of Oncolytic Polio/Rhinovirus Recombinant 
(PVSRIPO) in Recurrent WHO Grade IV Malignant Glioma Patients 
Protocol 
Number: 
Pro00077024  
Study Design: 
The purpose of this single-arm multicenter Phase 2 is to investigate the 
safety and efficacy (anti-tumor response and survival) of PVSRIPO in 
recurrent World Health Organization (WHO) grade IV malignant glioma. 
Patients will be administered PVSRIPO intratumorally via convection 
enhanced delivery (CED) and followed per the Schedule of Study Tests 
and Procedures for Initial PVSRIPO Treatment (Table 1). Retreatment 
with PVSRIPO is allowed, provided the retreatment eligibility criteria are 
met. Patients retreated with PVSRIPO will be followed per the Schedule 
of Study Tests and Procedures for PVSRIPO Retreatment (Table 2).   
Phase: 
Phase 2  
 
Objectives: 
Primary Objective: 
• 
To estimate the objective anti-tumor response rate and response 
duration among adults with recurrent WHO grade IV malignant 
glioma treated with PVSRIPO 
Secondary Objectives: 
• 
To assess the safety of PVSRIPO 
• 
To assess survival outcomes of adults with recurrent WHO grade 
IV malignant glioma treated with PVSRIPO relative to a historical 
control group  
• 
To assess the disease control rate following PVSRIPO infusion 
Exploratory Objectives: 
• 
To describe changes visualized on imaging due to intratumoral 
inoculation of PVSRIPO 
• 
To assess immunologic responses in peripheral blood and in 
serum 
• 
To identify genetic predictors of response or failure of response 
to treatment with PVSRIPO 
• 
To obtain the quantitative gut microbiome profile via the 
OMNIgene®•GUT (OMR-200) kit to determine any potential 
influence in response to PVSRIPO 
• 
To explore future molecular genetic analyses of the buffy coat to 
determine the genetic characteristics of these samples to 
determine any potential influence in response to PVSRIPO 
• 
As part of a smaller sub-study only at DUMC, subjects enrolled at 
this center may have blood drawn prior to PVSRIPO infusion 
(both pre- and post-PV booster) and 1 week after PVSRIPO 
infusion to explore inflammation-associated biomarkers, immune 
cell phenotype and innate and adaptive immune competence 
• 
Assess anti-tumor responses and outcomes following PVSRIPO 
retreatment(s) or treatment with any other non-protocol specified 
therapy 


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• 
Assess anti-tumor responses and outcomes considering site-
level experience with PVSRIPO treatment 


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Anticipated 
Number of 
Patients: 
Up to approximately 122 participants   
Anticipated 
Number of Study 
Sites: 
Up to 7 sites  
Follow-Up 
Duration: 
Up to 5 years, or until death, lost to follow-up, or withdrawal of consent 
(whichever comes first). 


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Entry Criteria: 
GENERAL INCLUSION/EXCLUSION CRITERIA 
INCLUSION CRITERIA: 
1. Patients must have a recurrent (first or second recurrence only, 
including this recurrence; transformation from a lower grade 
tumor to a WHO grade IV malignant glioma will be considered a 
first recurrence) supratentorial WHO grade IV malignant glioma 
based on imaging studies with measurable disease (a minimum 
measurement of 1 cm and maximum of 5.5 cm of contrast-
enhancing tumor) with prior histopathology consistent with a 
WHO grade IV malignant glioma confirmed by the site’s 
neuropathologist or the neuropathologist’s designate. 
a. Assuming patient meets all other criteria, site 
neurosurgeon must confirm placement of infusion 
catheter tip can occur within or as close as possible to an 
enhancing region of tumor that is ≥ 1cm from ventricles 
and at a safe distance relative to eloquent brain function. 
b. Tumor size and location requirements per protocol must 
be confirmed as qualifying and safe to proceed by the 
reviewer(s) designated by the Sponsor. 
2. If the subject is male and sexually active, he is eligible to enter 
and participate in this study if his partner(s) meets the criteria 
outlined in 2a or if he or his partner(s) is using one of the 
methods of birth control outlined in 2b. If the subject is female, 
she is eligible to enter and participate in this study if she meets 
the following criteria: 
a. Non-childbearing potential (ie, physiologically incapable of 
becoming pregnant, including any female who is 
postmenopausal or surgically sterile). Surgically sterile 
females are defined as those with a documented 
hysterectomy and/or bilateral oophorectomy or tubal 
ligation. Postmenopausal for purposes of this study, is 
defined as 1 year without menses); or 
b. Childbearing potential, has a negative serum pregnancy 
test at screening, and agrees to use one of the following 
methods of birth control: approved hormonal 
contraceptives (eg, birth control pills, patches, implants, 
or infusions), an intrauterine device, or a barrier method 
of contraception (eg, a condom or diaphragm) used with 
spermicide. 
c. If the male has had a vasectomy or is using a condom 
with spermicide, the female partner does not need to use 
additional birth control noted in 2a and 2b. 
3. Age ≥ 18 years of age at the time of entry into the study. 
4. Karnofsky Performance Status (KPS) Score ≥ 70%. 
5. Prothrombin and Partial Thromboplastin Times ≤ 1.2 x normal 
prior to biopsy. 
6. Total bilirubin, serum glutamic oxaloacetic transaminase (SGOT), 
serum glutamic pyruvic transaminase (SGPT), alkaline 
phosphatase ≤ 2.5 x normal prior to biopsy. 
7. Neutrophil count ≥ 1000 prior to biopsy. 
8. Hemoglobin ≥ 9 prior to biopsy. 


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9. Platelet count ≥ 100,000/µL unsupported is necessary for 
eligibility on study; however, because of risks of intracranial 
hemorrhage with catheter placement, platelet count ≥ 125,000/µL 
is required for the patient to undergo biopsy and catheter 
insertion, which can be attained with the help of platelet 
transfusion. 
10. Creatinine ≤ 1.2 x normal range prior to biopsy. 
11. Positive serum anti-PV titer prior to biopsy. 
12. The patient must have received a boost immunization with 
trivalent inactivated IPOL™ (Sanofi-Pasteur) at least 1 week, but 
less than 6 weeks, prior to administration of the study agent 
(initial infusion). 
13. At the time of biopsy, prior to administration of virus, the 
presence of recurrent tumor must be confirmed by 
histopathological analysis. 
14. A signed informed consent form (ICF) approved by the IRB will 
be required for patient enrollment into the study. Patients or their 
legally authorized representative (LAR) must be able to read and 
understand the informed consent document and must sign the 
informed consent indicating that they are aware of the 
investigational nature of this study. 
15. Able to undergo brain MRI with and without contrast. 
 
EXCLUSION CRITERIA: 
1. Females who are pregnant or breast-feeding. 
2. Patients with an impending, life-threatening cerebral herniation 
syndrome, based on the assessment of the study 
neurosurgeons, their designate, and the reviewer designated by 
the sponsor. 
3. Patients with severe, active co-morbidity, defined as follow: 
a. Patients with an active infection requiring intravenous 
treatment or having an unexplained febrile illness (Tmax 
> 99.5°F/37.5°C) 
b. Patients with known immunosuppressive disease or 
known human immunodeficiency virus infection 
c. Patients with unstable or severe intercurrent medical 
conditions such as severe heart disease (New York Heart 
Association Class 3 or 4) 
d. Patients with known lung (forced expiratory volume in the 
first second of expiration [FEV1] < 50%) disease or 
uncontrolled diabetes mellitus 
e. Patients with albumin allergy 
f. 
Patients with existing or history of anaphylactic reaction to 
gadolinium  
4. Patients with a previous history of neurological complications due 
to PV infection. 
5. Patients who have not recovered from the toxic effects of prior 
chemo- and/or radiation therapy. Guidelines for this recovery 
period are dependent upon the specific therapeutic agent being 
used. 


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6. Patients may not have received tumor treating fields (≤ 1 week), 
chemotherapy or bevacizumab ≤ 4 weeks [except for nitrosourea 
and lomustine (≤ 6 weeks); metronomic dosed chemotherapy, 
such as daily temozolomide, etoposide or cyclophosphamide (≤ 1 
week)] prior to starting the study drug. 
7. Patients may not have received immunotherapy ≤ 4 weeks prior 
to starting the study drug unless patients have recovered from 
side effects of such therapy. 
8. Patients may not be less than 12 weeks from radiation therapy of 
the brain, unless progressive disease outside of the radiation 
field or 2 progressive scans at least 4 weeks apart or 
histopathologic confirmation. 
9. Prior to enrollment, has not completed all standard of care 
treatments, including surgical procedure and radiation therapy (at 
least 59Gy) 
a. If the MGMT promoter in their tumor is known to be 
unmethylated, patients are not mandated to have 
received chemotherapy prior to participating in this trial 
b. If the MGMT promoter in their tumor is known to be 
methylated or the MGMT promoter methylation status is 
unknown at time of screening, patients must have 
received at least one chemotherapy regimen prior to 
participating in this trial 
c. If enrolling at 2nd recurrence, must have failed treatments 
initiated at 1st recurrence 
10. Patients with neoplastic lesions in the brainstem, cerebellum, or 
spinal cord; radiological evidence of multiple areas of active 
(growing) disease (active multifocal disease); tumors with 
contrast-enhancing tumor component crossing the midline 
(crossing the corpus callosum); extensive subependymal disease 
(tumor touching subependymal space is allowed); or extensive 
leptomeningeal disease (tumor touching leptomeninges is 
allowed). 
11. Patients with undetectable anti-tetanus toxoid immunoglobulin G 
(IgG). 
12. Patients with known history of agammaglobulinemia. 
13. Patients on greater than 4 mg per day of dexamethasone within 
the 2 weeks prior to admission for PVSRIPO infusion. 
14. Patients with worsening steroid myopathy (history of gradual 
progression of bilateral proximal muscle weakness, and atrophy 
of proximal muscle groups). 
15. Patients with prior, unrelated malignancy requiring current active 
treatment with the exception of cervical carcinoma in situ and 
adequately treated basal cell or squamous cell carcinoma of the 
skin. 
16. For patients randomized prior to v7, a known history of 
hypersensitivity to lomustine, dacarbazine, or any components of 
lomustine.  
17. Patients with active autoimmune disease requiring systemic 
immunomodulatory treatment within the past 3 months. 
 


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PVSRIPO RETREATMENT ELIGIBILITY CRITERIA: 
To be eligible for PVSRIPO retreatment(s), patients must continue to 
satisfy all general inclusion and exclusion criteria, including the following 
IC/EC adaptations/additions:  
1. Adaptation to Inclusion Criterion (IC) 1: Histologically confirmed 
(≤ 3 months of planned treatment) measurable (≥ 1 cm and ≤ 5.5 
cm of contrast-enhancing) supratentorial primary brain tumor that 
has recurred/progressed ≥ 12 months after initial PVSRIPO 
infusion 
2. Adaptation to IC 12: New boost immunization with trivalent 
inactivated IPOL™ (Sanofi-Pasteur) ≥ 1 week, but ≤ 6 months 
prior to PVSRIPO retreatment 
3. Addition: No treatment-limiting signs and symptoms (eg, cerebral 
edema) from prior PVSRIPO administration, such that PVSRIPO 
retreatment should be well tolerated, in the opinion of the 
investigator/neurosurgeon 
Investigational 
Product: 
PVSRIPO: recombinant, non-pathogenic chimera consisting of the 
genome from live-attenuated serotype 1 (Sabin) polio virus (PV1S) 
recombined with the internal ribosomal entry site (IRES) of human 
rhinovirus type 2 (HRV2). 
Dosage:  
5 x 107 tissue culture infectious dose (TCID50) in 3ml of physiologic 
saline stabilized with 0.2% human serum albumin (HSA) 
Route: 
Delivered intratumorally by convection-enhanced delivery (CED) over 
6.5 hours via intracerebral catheter  
Statistical 
Methods: 
The primary endpoint of overall radiographic response (ORR) will be 
presented as a percentage, along with a 95% confidence interval. 
Duration of response (DOR), overall survival (OS) and landmark survival 
(LS) will each be described according to the statistical analysis plan 
(SAP). Descriptive statistics will be presented for all other analyses 
unless otherwise specified. 
Interim Analysis: 
An interim analysis will be conducted after approximately 50 or more 
PVSRIPO-treated patients have been followed for approximately 21 or 
more months (details described in the statistical analysis plan).   
 
 
 
 


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Table 1. Schedule of Study Tests and Procedures for initial PVSRIPO Treatment 
Description 
Screening: 
Within 
6 weeks 
Screening: 
Within 
14 days 
prior to 
catheter 
placement, 
but as 
close to 
biopsy as 
possible 
Screening: 
Within 
2 days 
prior to 
PVSRIPO 
Catheter 
placement 
biopsy, 
PVSRIPO 
infusion 
Post-infusion (follow-up period)a 
On-Study 
Subjects 
(required SOC 
visits and 
minimum 
follow-up) 
Off-Study Subjects 
(SOC visits with follow-
up) 
Week 
 
 
 
 
0 
1 
2 
4 
8 
[WEEK 12 
VISIT 
REMOVED 
IN 
PROTOCOL 
V7] 
12b 
16 
+ every 
9 weeks 
until 
week 52 
>52 
(Information 
transmitted 
routinely as 
obtained) 
From time off study while 
available for follow-up 
(Information transmitted 
a minimum of every 6 
months [±1 month]) 
Day 
 
Within 
14 days 
prior to 
catheter 
placement 
Within 
2 days 
prior to 
PVSRIPO 
0 
1 
7 
14 
28 
56 
84 
112 
>112 
Varies 
General Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical assessment 
(including medical 
history) 
 
X 
 
 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination 
 
X 
 
 
Xc 
X 
X 
X 
X 
X 
X 
X 
 
Neurologic 
examination 
 
X 
 
Xc 
X 
X 
X 
X 
X 
X 
X 
 
KPS 
 
X 
 
 
Xc 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
 
 
 
Continuous 
 
Laboratory 
Evaluations 
 
 
 
 
PV immunization 
booster d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with 
differential 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
CMP 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
PT, aPTT 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy 
test 
 
X 
X 
 
 
 
 
 
Xe 
 
 
 
 


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Description 
Screening: 
Within 
6 weeks 
Screening: 
Within 
14 days 
prior to 
catheter 
placement, 
but as 
close to 
biopsy as 
possible 
Screening: 
Within 
2 days 
prior to 
PVSRIPO 
Catheter 
placement 
biopsy, 
PVSRIPO 
infusion 
Post-infusion (follow-up period)a 
On-Study 
Subjects 
(required SOC 
visits and 
minimum 
follow-up) 
Off-Study Subjects 
(SOC visits with follow-
up) 
Week 
0 
1 
2 
4 
8 
[WEEK 12 
VISIT 
REMOVED 
IN 
PROTOCOL 
V7] 
12b
16 
+ every
9 weeks
until
week 52
>52
(Information
transmitted
routinely as
obtained)
From time off study while 
available for follow-up 
(Information transmitted 
a minimum of every 6 
months [±1 month]) 
Day 
Within 
14 days 
prior to 
catheter 
placement 
Within 
2 days 
prior to 
PVSRIPO 
0 
1 
7 
14 
28 
56 
84 
112 
>112
Varies 
Serum for LSQ, 
anti-tetanus toxoid 
IgG 
X (pre-
boost) 
PV titerf 
X (pre-
boost) 
Whole blood for 
immunologic/other 
analysisg 
X (pre-
boost) 
X 
Xg 
Xh
X 
X 
Whole blood for 
buffy coat isolation 
X 
Stool sample n 
X n 
Xn 
Disease evaluations 
MRIi 
X 
X 
X 
X 
X 
X 
CT scan 
Xj
Biopsyk 
X 
Tumor samples 
Xl 
Xl 
Treatment 
PVSRIPO 
X (+ 1-day 
window) 
Lomustine 
Xm 
aPTT = activated partial thromboplastin time; CBC = complete blood count; CMP = Comprehensive Metabolic Panel; CT = computed tomography; IgG = immunoglobulin G; 
KPS = Karnofsky Performance Status; LSQ = lymphocyte subset quantitation; MRI = magnetic resonance imaging; PT = prothrombin time; PV = poliovirus; 
PVSRIPO = polio/rhinovirus recombinant; SAM = Study Administration Manual; SOC = standard of care. 
a Tests and procedures occurring on Day 7 have a ± 3-day window. From Day 14 (Week 2) onward, all tests and procedures have a ± 7-day window. 


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b The week 12 clinic visit (± 1 week) and whole blood collection for immunologic/other analysis was removed in protocol v7, as it was associated with follow-up after lomustine use. 
Patients enrolled under protocol version 7 and after will not have a protocol mandated week 12 visit. 
c Daily after infusion until discharged from hospital; a PE must be documented within 24h (±4h) of discharge. 
d PV booster must occur ≥ 1 week (but ≤ 6 weeks) prior to the initial PVSRIPO infusion. 
e Only for women of childbearing potential who are randomized to receive lomustine prior to protocol V7. 
f For screening prior to initial PVSRIPO infusion, PV titers are to be drawn after informed consent and prior to PV booster administration. No additional tubes need to be drawn for the 
PV titer. This analysis can be done from the whole blood drawn for immunologic analysis. 
g Whole blood for immunologic analysis (3mL at Day 1 OR Day 2 post-PVSRIPO infusion; thereafter, ~96.5 mL; tube and sample processing and shipping details outlined in laboratory 
manual portion of the SAM). For patients only at DUMC, an additional 6ml (~102.5 mL total) will be drawn at both the pre-PV boost and post-PV screening visits (before PVSRIPO 
infusion) and again at the Week 1 visit as part of a sub-study at DUMC to explore inflammation-associated biomarkers, immune cell phenotype and innate and adaptive immune 
competence. After Week 8, only draw 76.5 mL of whole blood for all patients/all centers. 
h Blood sample (6mL) collected on Day 7 (Week 1) post-infusion only for participants enrolled at DUMC consented to sub-study for immune marker analyses. 
i All MRIs in the study include intravenous administration of gadolinium. After week 52, MRIs are to be conducted per the institution’s SOC and all images are to be transmitted to the 
sponsor or their designee no less than every 6 months (± 1 month) after the last images were transmitted. 
j There is a post-catheter placement CT scan and a post-catheter removal CT scan. 
k Biopsy results should be transmitted, or blocks/slides should be shipped to the sponsor or designee per instructions in the laboratory manual portion of the SAM. 
l If any additional samples become available or resections occur anytime during the study (make patient off study) or off-study follow-up period, materials also should be transmitted to
the sponsor or their designee, as outlined in the SAM, if possible.
m For subjects randomized to the lomustine cohort prior to protocol v7 received 110 mg/m2 oral lomustine for one cycle at 8 weeks post-PVSRIPO infusion. Subjects who were on 
bevacizumab (were treated with bevacizumab in the time since PVSRIPO infusion) received 90 mg/m2 oral lomustine for one cycle 8 weeks post-PVSRIPO infusion. The lomustine 
may have been taken the day of or 1 day after the week 8 visit. 
n Stool Sample for OMNIgene Kit (OMNIgene®•GUT (OMR-200)). For newly enrolled patients (ie, those who have not received PVSRIPO under a previous protocol version), a kit will 
be dispensed at the pre-PV boost screening visit and they will provide a baseline sample prior to PVSRIPO infusion and again after the week 8 visit. For patients who received 
PVSRIPO under a previous version of the protocol, a baseline/pre-PVSRIPO sample will not be obtained but the patient will be given a kit to provide a post-PVSRIPO infusion stool 
sample at their next clinic visit.  


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Table 2. Schedule of Study Tests and Procedures for PVSRIPO Retreatment 
AEs = adverse events; aPTT = activated partial thromboplastin time; CBC = complete blood count; CMP = comprehensive metabolic panel; CT = computed tomography; 
IgG = immunoglobulin G; KPS = Karnofsky Performance Status; LSQ = lymphocyte subset quantitation; MRI = magnetic resonance imaging; PT = prothrombin time; PV = poliovirus; 
SAE = serious adverse events 
aInformed Consent must be renewed prior to initiation of screening activities for PVSRIPO retreatment. 
bFollow-up beyond Week 52 post retreatment: participants should be followed per institutional SOC for all assessments after Week 52 post PVSRIPO retreatment. Data transfers 
should occur no > every 3 months (including description of MRI/tumor measurements). If SOC occurs less frequently, data should be entered within 2 weeks (± 1 week) of acquisition. 
cPhysical Examination: The screening physical examination should be a complete physical exam of major body systems, per institutional guidelines. Following PVSRIPO infusion, 
physical exams should be focused and symptom-directed. Each exam should be performed in conjunction with a neurological exam and KPS assessment.  
Study Procedure 
Screening 
Period 
PVSRIPO 
infusion 
Post-infusion (follow-up period) 
≤ 14 days 
Day 0 
Day 1 
1w 
(+/- 3d) 
2w 
(+/- 1w) 
4w 
(+/-1w) 
8w 
(+/-1w) 
Q9-12w for 52w 
> 52 weeks
from
Retreatmentb 
Informed Consenta 
X 
Clinical assessment & medical 
history 
X 
Xd 
X 
X 
X 
X 
X 
X 
Physical Examc 
X 
Xd 
X 
X 
X 
X 
X 
X 
Neurologic Exam 
X 
Xd 
X 
X 
X 
X 
X 
X 
KPS 
X 
Xd 
X 
X 
X 
X 
X 
X 
Record Cancer treatments & 
Concomitant medicationse 
Continuous from signing of ICF onward 
Adverse Events 
Continuous 
PV Immunization Booster and 
anti-tetanus IgGf 
X 
CBC w/diff 
X 
X 
X 
X 
X 
X 
X 
CMP 
X 
X 
X 
X 
X 
X 
X 
PT, aPTT 
X 
Pregnancy Testg 
X 
MRI 
X 
X 
X 
X 
X 
CT Scan 
Xh 
Biopsy 
X 
PVSRIPO 
X 


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dPost-PVSRIPO (re)treatment: Clinical assessment and physical examinations (including neurologic assessment and KPS) should be performed daily until hospital discharge.  
eCancer Treatments and Concomitant Medications: all start/stop dates, dose, route, frequency, procedures and treatments for glioma or any other cancer treatment are to be 
recorded from baseline onward, including agents associated with managing PVSRIPO anti-tumor inflammatory response (ie, corticosteroids and bevacizumab) or for any other 
agents/causes.   
fPolio immunization booster and anti-tetanus toxoid IgG blood test: May be obtained locally and must occur ≥ 1 week (but ≤ 6 months) prior to planned additional PVSRIPO 
infusion(s). 
gPregnancy Test: A serum-based pregnancy test must be performed for all female participants during screening (≤ 2 days of PVSRIPO infusion). 
hCT Scan: Includes a CT to confirm catheter placement prior to PVSRIPO infusion (preferably intraoperative) and second CT upon catheter removal to confirm no bleed.




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machinery, which stimulates viral, cap-independent translation via the HRV2 IRES in 
cancerous cells. 
 
In a phase 1 dose-finding study that enrolled patients with recurrent grade IV malignant 
glioma, PVSRIPO was well tolerated, with dominant adverse effects being 
complications from localized tumor inflammation and the secondary prolonged use of 
steroids, particularly at higher doses of PVSRIPO. To limit these effects, the dose was 
de-escalated, and the trial continued as a dose expansion study. The trial closed to new 
accrual on 5/31/2017. There has been no evidence of propagation of infectious virus 
beyond the tumors in these patients nor evidence of viral encephalomyelitis, 
poliomyelitis, meningitis, or systemic autoimmune reactions. There is evidence that, in 
addition to a direct cytotoxic effect of PVSRIPO on infected tumor cells, this treatment 
generates an immune response against the tumor itself, which can lead to a reduction in 
tumor size. The localized inflammatory response is observed on imaging, and, as 
observed with other immunotherapies, it is difficult to distinguish between localized 
inflammation and tumor progression. In some subjects with possible disease 
progression observed by imaging after PVSRIPO infusion, the decision was made to 
treat with temozolomide or lomustine. A number of patients treated with temozolomide 
or lomustine after PVSRIPO infusion showed a rapid decrease in tumor volume after 
initiation of chemotherapy. However, this tumor control was lost in some patients if they 
remained on therapy for a prolonged period. Immune monitoring in a limited number of 
patients showed: 1) contraction of a specific, high-impact subset of 
(immunosuppressive) T-regulatory cells; and 2) beginning expansion of effector T-cells 
at the nadir (4 weeks post lomustine). Any such beneficial effect is likely to be lost upon 
standard multicycle chemotherapy, as subsequent lymphodepletions will eventually 
dampen the immune system’s capacity to target the tumor. 
 
Therefore, in this study, we initially proposed to evaluate a single intratumoral 
administration of PVSRIPO in combination with a single cycle of lomustine 8 weeks 
post-PVSRIPO instead of the standard 9-cycle/1-year regimen for the following reasons: 
a) Information stemming from patients treated with lomustine post-PVSRIPO on a 
phase 1 clinical protocol suggests significant clinical response, radiographic response, 
and the involvement of an antitumor immune component (ie, a PVSRIPO-induced 
antitumor memory response) occurring after the first cycle, with no evidence for further 
benefit with additional cycles of lomustine thereafter; b) this is in line with much 
empirical evidence for beneficial effects of lymphodepletion with DNA-damaging 
chemotherapy, eg lomustine or temozolomide, in conjunction with immunotherapy 
regimens. Lymphodepletion is believed to generate an ‘immunologic reset’ by broadly 
eliminating suppressive T-cell subsets and favoring preferential expansion of T-cell 
populations with pro-inflammatory activation phenotypes during immune recovery. While 
the immunologic benefits of lymphodepletive chemotherapy is well documented, it is 
equally well known that standard cycle-therapy (eg with one year of lomustine) 
produces long-term immune suppression by abrogating the expansive phase of immune 
recovery following the initial cycle of lomustine4. However, a preliminary review of safety 
and related information of 50 patients treated on study (24 on the PVSRIPO only arm 
and 26 on the PVSRIPO with lomustine arm) was conducted and there was no apparent 






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6 
STUDY SCHEMA 
 
*Exception: short term use of 7.5mg/kg 
bevacizumab, if needed, to manage 
cerebral edema or PVSRIPO 
retreatment as noted in Section 5.2 
*PVSRIPO 
Retreatment allowed 
at progression if ≥ 12 
months from initial 
infusion/eligible per 
protocol 




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7.2.2 PVSRIPO Oncolysis 
PVSRIPO’s anti-neoplastic potential is due to a series of (i) direct lytic effects on tumor 
cells; (ii) presentation of tumor-associated antigens in a highly adjuvanted context; (iii) 
pro-inflammatory and danger signals stemming from tumor destruction and activation of 
an antiviral type 1 interferon response; (iv) infection and pro-inflammatory activation of 
dendritic cells and tumor-associated macrophages; (v) durable antitumor immunity 
evoked by effector cytotoxic T lymphocyte responses (Figure 2)21. The principal 
elements determining PVSRIPO tumor tropism, tumor-specific cell killing, neuronal 
incompetence/safety, and immunogenicity are well established empirically21,22. 
Figure 2. Pathways involved in PVSRIPO oncolytic immunotherapy. PVSRIPO oncolytic immunotherapy is 
based on combined cytotoxic and immunogenic effects on tumor cells (left), pro-inflammatory effects on 
antigen-presenting cells (middle) and the generation of adaptive antitumor immunity (right). 
7.2.3 PVSRIPO Tumor Tropism 
Every aspect of PVSRIPO oncolytic immunotherapy is dominated by its relationship with 
its host cell receptor, CD15523. CD155 is broadly expressed in neuroectodermal 
malignancies, eg, malignant glioma. Its expression has been empirically confirmed in 
laboratory malignant glioma cell lines, primary patient explant malignant glioma cells, 
primary patient explant malignant glioma xenografts maintained in athymic mice, and 
patient malignant glioma tissues obtained during surgery24. CD155 is expressed on 
tumor cells proper, on proliferating tumor vascular cells, and on macrophages and 
dendritic cells25,26. 
7.2.4 PVSRIPO Tumor-Specific Cell Killing 
Infection of tumor cells with PVSRIPO results in their swift destruction, due to very early 
translation of highly cytotoxic viral proteins immediately after entry of the viral 
ribonucleic acid (RNA) into infected host cells27. PVSRIPO achieves this through an 


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unorthodox mechanism of translation initiation28. At eukaryotic mRNAs, protein 
synthesis occurs upon recruitment of a multi-partite protein complex at the canonical 5’ 
‘cap’ structure. PV RNAs are un-capped and, hence, rely on cap-independent 
translation for viral protein synthesis. This involves direct recruitment of ribosomal 
subunits via binding of the eukaryotic initiation factor (eIF) 4G to viral RNA (Figure 1)29. 
eIF4G-binding occurs via the IRES, a cis-acting genetic element located in the 5’ 
untranslated region of the viral RNA. In tumor cells, this process is highly efficient, due 
to un-hinged signal transduction networks that greatly favor ribosome recruitment to 
viral RNA. 
PVSRIPO is deemed acceptable for investigation in humans, including after 
intracerebral inoculation, because it is incapable of driving viral translation in normal 
brain cells17. This is due to profound neuronal incompetence of the foreign HRV2 IRES 
in its genome. The foreign HRV2 IRES cannot recruit eIF4G to the viral genome, 
precluding viral protein synthesis in neuronal cells/the normal brain30. By blocking this 
crucial, early step in the infectious cycle specifically in neurons, PVSRIPO 
neurovirulence is eliminated. 
7.2.5 PVSRIPO Pre-Clinical Experience 
In animal tumor models, oncolytic PVs elicit efficient anti-neoplastic effects resulting in 
tumor regression and, eventually, destruction27. There is histologic evidence for direct, 
virus-mediated tumor cell killing and indirect, host-mediated inflammatory responses 
directed against tumor. PVSRIPO was subjected to extensive dose-range finding, 
toxicology, biodistribution, shedding and neutralizing antibody tests with intrathalamic 
inoculation of up to 5 x 109 TCID50 of PVSRIPO in M. Fascicularis31. These revealed: (i) 
absence of morbidity and mortality; (ii) absence of neuropathological signs consistent 
with virus-induced CNS damage; (iii) absence of virus dissemination from the brain or 
viremia; (iv) absence of extraneural replication; (v) absence of shedding with saliva, 
urine or stool; (vi) presence of a neutralizing antibody response. 
7.2.6 PVSRIPO Clinical Experience 
The first-in-human oncolytic PV, PVSRIPO, therapy was initiated at the Preston Robert 
Tisch Brain Tumor Center (PRTBTC) at Duke University Medical Center (DUMC) in 
early 2012 as a phase 1 trial in patients with histologically confirmed recurrent WHO 
grade IV malignant glioma (glioblastoma or gliosarcoma; size of 1-5.5 cm). The study 
was closed to accrual on 5/31/2017 after 61 patients were treated. Key inclusion criteria 
in this clinical trial included: ≥ 18 years, adequate performance status/organ function, 
and prior PV immunity. Key exclusion criteria included: pregnant/breast-feeding 
females, those who have received radiotherapy less than 12 weeks prior, and those 
with known immune dysfunction or febrile and/or other systemic illnesses. Patients were 
given a booster of inactivated PV vaccine ≥1 week, but not > 6 months, prior to 
PVSRIPO infusion. Consented patients first underwent biopsy of the lesion to confirm 


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recurrence and then have a catheter placed into the tumor ≥ 1 cm away from the 
ventricles. The catheter was tunneled 5 cm under the scalp and connected to an 
infusion pump. The agent was then infused at a rate of 0.5 mL/hr over a period of 6.5 
hours. In the investigational new drug (IND) toxicology studies in NHPs, no dose-limiting 
toxicities were observed, and the maximum tolerated dose was not reached. The 
starting dose in this first-in-human trial was 1 x 108 TCID50, which is 1/10th of the 
highest non-toxic dose in NHPs from the definitive, IND-directed toxicology study and 
1/50th of the highest non-toxic dose in NHPs from the dose-range finding toxicology 
study. In the dose escalation portion of the phase 1 trial, cohorts of patients were dosed 
at 1 x 108 TCID50 (dose level 1), followed by 3.3 x 108 (level 2), 1 x 109 (level 3), 3.3 x 
109 (level 4), and 1 x 1010 (level 5). The rationale and outcome associated with 
subsequent dose reductions to 3.3 x 108 (level 2), 5 x 107 (level -1), and 1.0 x 107 (level 
-2) are described below.
Dose Escalation Phase: The first 9 patients, who were treated at dose levels 1 through 
5, constituted the dose escalation portion of the study. One patient each was treated at 
dose levels 1 through 3, 2 patients at level 4, and 4 patients at level 5. One of four 
patients treated at dose level 5 suffered a dose-limiting toxicity of intracranial 
hemorrhage after catheter removal. This subject was removed from study seven months 
post-infusion, when he started treatment with lomustine for pathology confirmed tumor 
recurrence, per protocol guidelines. The subject was still alive (as of 5/31/2017) and 
remained disease free for an extended period following initial treatment with PVSRIPO 
followed by the lomustine (approximately 43 months) but has since been re-treated with 
a second infusion of PVSRIPO at dose level -2 due to evidence of a new lesion. 
Three other patients at dose level 5 died of progressive disease 12-20 months post-
treatment and had difficulty weaning down steroids following study drug administration 
due to cerebral edema possibly due to localized inflammation and/or progressive 
disease. As of 5/31/2017, the 2 patients treated at dose level 1 and 2 did not suffer any 
significant toxicities and were alive with “No Evidence of Disease” 61+ and 60+ months 
from treatment, respectively. The patient at dose level 3 and one patient at dose level 4 
died of progressive disease 6 months post-infusion, and one patient at dose level 4 died 
at 16 months post-treatment. Due to observed tumor inflammation at the higher dose 
levels that could potentially have been related to treatment or tumor growth, which 
necessitated prolonged steroid use, the dose was de-escalated and six additional 
patients were treated at dose level 2, as part of the dose expansion phase. In this 
cohort, one patient died 7 months following therapy after suffering an intracerebral 
hemorrhage due to head injury from a fall. Five other patients have all died of 
progressive disease 6-16 months following treatment. 
Dose Reductions to Dose Level -1 and -2: Due to the continuing requirement for 
steroids in all of the additional patients treated at dose level 2 because of localized 
inflammation, due to treatment and/or tumor growth, a decision was made to de-
escalate to dose level -1 (5 x 107 TCID50). By 6/16/2016, twenty-four patients had been 
treated at dose level -1, including 12 patients that were treated more than 12 months 
prior. Three of these 12 subjects demonstrated tumor reduction without significant 




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tropism for tumor cells by virtue of expression of CD155 in tumor cells. To facilitate 
concentration of the therapeutic agent at the tumor site, while minimizing systemic 
exposure, PVSRIPO will be delivered directly into the tumor. Significant pre-clinical 
antitumor activity of PVSRIPO has been observed in several rodent tumor models and 
in vitro. PVSRIPO was devoid of neuropathogenicity when injected into the thalami of 
NHPs even at doses as high as 5 x 109 TCID50. Also, the phase 1 trial of PVSRIPO in 
adults with recurrent WHO grade IV malignant glioma did not yield evidence of viral 
encephalomyelitis, poliomyelitis or meningitis with a proportion of patients achieving 
prolonged disease survival up to 92+ months. The main toxicity attributable to PVSRIPO 
has been post-treatment peri-tumoral inflammation that has required prolonged steroid 
therapy and/or low-dose bevacizumab to control edema. 


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8 
OBJECTIVES AND ENDPOINTS 
Objective 
Endpoint 
Analysis 
Primary 
Assess the anti-tumor 
response and duration of 
response among adults with 
recurrent WHO grade IV 
malignant glioma treated 
with PVSRIPO 
ORR: defined as the proportion 
of patients achieving Complete 
Response (CR) or Partial 
Response (PR) based on iRANO 
criteria 
DOR: defined as time from CR or 
PR until confirmed Progressive 
Disease (PD) 
See Section 14.5 
Secondary 
Assess survival outcomes of 
adults with recurrent WHO 
grade IV malignant glioma 
treated with PVSRIPO 
relative to a criteria matched 
external (historical) control 
group 
Landmark Survival: the 
proportion of patients alive 
starting ≥ 36 months after 1st 
PVSRIPO infusion  
OS: defined as time from 
PVSRIPO infusion to death from 
any cause, or last follow-up if 
patient is alive 
See section 14.6 
Secondary 
Assess the safety of 
PVSRIPO 
The proportion of patients with 
grade 3, 4, or 5 treatment-related 
adverse events 
See Section 14.6 
Secondary 
Assess the disease control 
rate following PVSRIPO 
infusion 
Disease Control Rate (DCR): 
defined as the proportion of 
patients deemed non-
progressive based on imaging 
criteria described in the Central 
Imaging Charter 
See Section 14.6 
Exploratory 
Describe changes visualized 
on imaging due to 
intratumoral inoculation of 
PVSRIPO 
Description of imaging changes 
See Section 14.7 
Exploratory 
Assess immunologic 
responses in peripheral 
blood and in serum 
Change from baseline in immune 
function 
See Section 14.7 
Exploratory 
Identify genetic predictors of 
response or failure of 
response (including in buffy 
coat) to treatment with 
PVSRIPO 
Identification of genetic markers 
as predictors of response 
See Section 14.7 
Exploratory 
To obtain the quantitative 
gut microbiome profile via 
the OMNIgene®•GUT 
(OMR-200) kit to determine 
any potential influence in 
response to PVSRIPO 
Identification of quantitative gut 
microbiome profile as predictors 
of response 
See Section 14.7 
Exploratory 
As part of a smaller sub-
study only at DUMC, to 
explore inflammation-
associated biomarkers, 
immune cell phenotype and 
Inflammation-associated 
biomarkers, immune cell 
phenotype and innate and 
adaptive immune competence 
See Section 14.7 




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In the case of initial PVSRIPO infusion, if the biopsy for clinical pathologic diagnosis 
does not confirm recurrent tumor, the subject will be withdrawn from the study. Subjects 
in screening for retreatment whose biopsy does not confirm recurrence will not be 
retreated with PVSRIPO, but will remain on study in follow-up. 
 
The biopsy needle and catheter will be placed by the operating surgeon using an FDA 
cleared stereotaxic guidance system guided by a pre-operative MRI. After biopsy, a 
catheter [Vygon PIC-030 (Sophysa, Inc.; Crown Point, IN)] will be implanted in the 
operating room using sterile techniques, which may occur under general anesthesia, at 
the same site or a different site from that used for the biopsy. The catheter will be 
implanted within, or as close to, an enhancing region of tumor as possible ≥ 1 cm away 
from the ventricles. Based on prior experiences, a tumor ≤ 1cm from the ventricles can 
safely and feasibly have a catheter tip placed ≥ 1cm from the ventricles while minimizing 
the possibility of infusate entering the ventricles. The catheter will be tunneled beneath 
the scalp for a distance of at least 5 cm to aid in the prevention of infection. A computed 
tomography (CT) scan will be used to confirm catheter placement post-operatively. 
Anesthesia administration is discontinued once there is CT confirmation of the catheter 
placement, as applicable.  
 
Patients who are taking (and are stable on) less than or equal to 4 mg per day of 
dexamethasone (ie, low-dose corticosteroid) within the 2 weeks prior to admission for 
any PVSRIPO infusion (ie, patients who meet the relevant eligibility criterion) may 
continue on this dose. The administration of high-dose corticosteroids will be limited 
while on study due to concerns that high-dose corticosteroids might negatively impact 
the efficacy of PVSRIPO. However, high-dose corticosteroids may be administered on a 
limited basis to patients prior to, during, or after PVSRIPO infusion only when 
determined to be medically necessary. 
 
9.1.2 PVSRIPO Infusion 
 
The entire volume of the agent to be delivered will be pre-loaded into a syringe and 
connected to the catheter under sterile conditions in the appropriate clinical care unit 
(eg neurointensive care unit/intensive care unit or neuro step-down unit) just prior to 
beginning of infusion. Due to the complexity of scheduling all of the necessary 
components for the infusion (operating room time, pharmacy time, and radiology 
appointments), a +1 day window has been built into the study for the study drug 
infusion. This means that the infusion is allowed to start the following day after the 
biopsy/catheter placement. This will still be considered “day 0” in regard to the protocol 
and the timing of the subsequent events. At the time of virus injection, emergency 
drugs, including epinephrine and diphenhydramine will be available and the neurologic 
status, oxygen saturation, and cardiac rhythm will be monitored. Drug infusion will occur 
in the appropriate clinical care unit so that all other emergency facilities will be available. 
Patients will be treated with a prophylactic antibiotic prior to biopsy and catheter 
insertion per the institution’s neurosurgical standard practice. 
 


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Based on Duke’s experience, previously published reports33, and institutional review 
board (IRB) and FDA-approved trials using similar infusion techniques, patients will be 
infused at a rate of 0.5 mL/hr. A Medfusion™ 3500 infusion pump (Smiths Medical, 
Minneapolis, MN) or any other comparable FDA-cleared syringe infusion pump 
approved by the Sponsor or their designee, will be pre-programmed to a delivery rate of 
0.5 mL/hr. The infusate will be loaded in an infusion syringe into the syringe pump at the 
initial onset to avoid any interruptions in the infusion. The total amount of the infusate 
delivered to the patient will be 3 mL. The catheter itself (30 cm length, 1 mm interior 
diameter) cannot be pre-loaded with virus suspension. Therefore, the infusion pump will 
be programmed for delivery of 3.25 mL (0.25 mL to account for catheter “dead space” 
with 3.0 mL delivered to the patient). The infusion pump will be programmed for delivery 
of 0.5 mL/hr over approximately 6.5 hours (stopped when delivered amount is between 
3.125 and 3.250 mL). The catheter will be removed in the appropriate clinical care unit. 
No sedation is required for catheter removal. A non-contrasted CT scan of the brain will 
be used after catheter removal to confirm there is no bleed post catheter removal. 
The infusion catheter (PIC 030) and infusion tubing (PIT 400) are manufactured by 
Sophysa, Inc. (Crown Point, IN) and supplied to the sites according to the Study 
Administration Manual (SAM). The Infusion Catheter Kit is a 30 cm clear, open-ended 
catheter (1.0 mm ID/2.0 mm OD) with 1 cm markings for 20 cm. The catheter comes 
with a 30 cm stainless steel stylet, a barbed female luer lock with cap and a stainless 
steel trocar. The Infusion Tubing Kit consists of a 3-way stopcock connector with air 
filter, 4 m of microbore tubing with antisiphon valve, a red, vented cap and a white luer 
lock cap. The catheter products are packaged sterile and non-pyrogenic and are 
intended for single (one-time) use only (see the infusion procedures in the study 
procedure manual). 
Acute Reaction. Any reaction symptoms determined to be an acute reaction to the 
study drug will be managed by the appropriate clinical care unit. 
9.1.3 Gadolinium Distribution Quantitation 
Prior to protocol version 8, a non-contrasted MRI imaging, within 4 hours of the 
completion of infusion, was registered in an attempt to define the shape and position of 
the contrast agent distribution co-administered with PVSRIPO relative to the patient’s 
brain anatomy. While Gd-DTPA is a widely available MRI contrast agent, there has 
been speculation that its small molecular weight (938 Dalton) could limit its ability to 
predict the distribution of the larger molecules typically infused therapeutically with CED 
[reviewed in Reardon et al., 2011]34. Development of large molecule tracers labeled with 
gadolinium (Gd) has been problematic, but it has been stipulated that infusion of low 
molecular weight Gd-DTPA can predict the distribution of larger molecules by 
systematic post-infusion manipulation of the images based on theoretical differences in 
the predicted distribution of the Gd-DTPA and the therapeutic drug being infused35. This 
has been confirmed by simultaneously infusing a patient with a supratentorial recurrent 
malignant glioma with an epidermal growth factor receptor (variant III) (EGFRvIII)-


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targeted immunotoxin in combination with 124I-HSA [to permit positron emission 
tomography (PET) imaging] and Gd-DTPA. Gd-DTPA co-infusion provided direct 
information about the distribution of large molecules with high resolution35. In 
combination with fluid-attenuated inversion recovery (FLAIR) imaging, Gd-DTPA co-
infusion provides additional information about leak into cerebrospinal fluid spaces and 
resection cavities36. However, as of July 17, 2019, Magnevist®, which was added to the 
PVSRIPO infusate for tracking purposes, will no longer be manufactured nor be readily 
available in the US. This change was not related to product quality, safety, or efficacy 
(see: FDA website for more information). Therefore, for patients enrolled after 
10OCT2019, addition of Magnevist® to the infusate was not required and the 
corresponding post-infusion MRI to occur within 4 hour post-infusion in an effort to track 
infusate was also removed. 
9.1.4 Biopsy Sampling and Analyses 
9.1.4.1 
Study-Related Biopsy 
Prior to catheter placement and PVSRIPO infusion, a biopsy will be performed. The 
biopsy for the first PVSRIPO infusion will consist of taking multiple samples as 
described below. 
1. A tumor tissue sample will be collected for review via routine histology to confirm
tumor recurrence by the site neuropathologist(s) for confirmation of eligibility. For the
first PVSRIPO infusion only, the study’s central neuropathologist at Duke, Dr. R.
McLendon or his designee, will also provide a determination of histology upon
receipt of tissue, but this is not necessary for confirmation of eligibility. This will
require the sites to ship one H&E stained slide from the first PVSRIPO infusion
biopsy to DUMC (see pathology section of the SAM for additional information).
Additional unstained slides from this biopsy and others for subsequent PVSRIPO
infusion(s) may also be required, depending on the routine pathology/biomarker
tests that the site performs.
Additional pathology/biomarker tests that may be performed include, but are not 
limited to, the following: 
•
Anti-PV receptor
•
EGFRvIII and wild-type EGFR status
•
O6-methylguanine-DNA methyltransferase (MGMT) promoter
methylation and MGMT immunohistochemistry
•
Isocitrate dehydrogenase 1 and 2
•
Telomerase reverse transcriptase (TERT)
•
Programmed cell death protein 1 (PD-1)/programmed death-ligand
1 (PD-L1)
If any of these tests are routinely performed at the study site per standard of care 
practice, these tests will not be repeated at DUMC. In these instances, the sites will 


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enter their local pathology results into the electronic case report form (eCRF). For 
specific tests outlined in the pathology manual that are not run at the sites, unstained 
slides will be shipped to DUMC so that these tests can be conducted. Please see 
the pathology manual for the number and type of slides needed for each test. If a 
site would prefer to send a tissue block instead of unstained slides, that is permitted. 
If there is not enough tissue to perform all of these tests, the tests will be run in order 
of priority per the pathology manual. 
2. After acquiring sufficient tissue for standard clinical pathologic testing (#1), up to
three additional core biopsies will be obtained, if possible. These additional core
biopsies will be frozen in optimal cutting temperature compound and kept at liquid
nitrogen temperature. They will be used for genetic analysis, including full genome
or full exome sequencing, as well as other molecular genetic testing. The goal of
these molecular genetic tests is to identify genetic predictors of response or failure of
response to treatment with PVSRIPO. The molecular genetic testing will include, but
is not limited to, DNA sequencing, gene amplification, and gene expression. Please
see the pathology section of the SAM for information on core biopsy processing and
shipping.
9.1.4.2 
Archival Tissue 
Tissue samples from archival tissue, including initial surgical procedure where WHO 
grade IV malignant glioma was confirmed and any additional surgical procedures for 
recurrence prior to enrolling in the PVSRIPO clinical trial, will also be collected. These 
tissue samples may be tested for, but not limited to, the pathology/biomarkers listed in 
Section 9.1.4.1. Additionally, 10 unstained slides will be requested from each previous 
surgical procedure/biopsy for genetic analysis. 
If any of the pathology/biomarker tests mentioned in Section 9.1.4.1 are routinely 
performed at the study site per standard of care practice and the information is available 
for the applicable archival tissue, these tests will not be repeated at DUMC. In these 
instances, the sites will enter their local pathology results into the eCRF. For specific 
tests outlined in the pathology manual that are not run at the sites, unstained slides will 
be shipped to Duke so that these tests can be conducted. Please see the pathology 
section of the SAM for the number and type of slides needed for each test. If a site 
would prefer to send a tissue block instead of unstained slides, that is permitted. If there 
is not enough tissue to perform all of these tests, the tests will be run in order of priority 
per the pathology section of the SAM. 
9.1.4.3 
Future Surgical Procedures 
Administration of PVSRIPO is associated with an inflammatory immune response that 
can result in a pseudoprogressive tumor appearance on radiographic imaging. 
Following PVSRIPO administration, patients should not undergo tumor resection based 
on radiographic tumor progression, without prior consultation with the study-designated 


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neurooncologist(s) and/or ISC except in cases of eminent life-threatening emergency. 
Should subjects have a resection or biopsy after coming off study, each site will be 
responsible for requesting samples of this resected/biopsied tissue, which will then be 
sent to DUMC for pathology/biomarker tissue analysis. If a subject consents, portions of 
resected/biopsied tissue will be delivered to the DUMC study neuropathologist, Dr. R. 
McLendon or his designate, for histopathological analyses and to Dr. M. Gromeier or his 
designate for correlative molecular analyses. The histopathological analyses may 
include, but are not limited to, the same pathology/biomarker tests listed in Section 
9.1.4.1. The correlative molecular analyses will require 10 additional unstained slides. 
The histopathological and correlative molecular analyses will only occur if a sufficient 
amount of tissue remains after standard clinical pathologic testing. 
If any of the pathology/biomarker tests mentioned in Section 9.1.4.1 are routinely 
performed at the study site per standard of care practice for the samples collected from 
future surgical procedures, these tests will not be repeated at DUMC. In these 
instances, the sites will enter their local pathology results into the eCRF. For specific 
tests outlined in the pathology manual that are not run at the sites, unstained slides will 
be shipped to DUMC so that these tests can be conducted. Please see the pathology 
section of the SAM for the number and type of slides needed for each test. If a site 
would prefer to send a tissue block instead of unstained slides, that is permitted. If there 
is not enough tissue to perform all of these tests, the tests will be run in order of priority 
per the pathology section of the SAM. 
In addition, in the event of subject death during or after participation in this study, 
permission from the subject and next-of-kin to obtain the subject’s brain and conduct a 
post-mortem examination will be requested. 
9.1.5 Lomustine (PVSRIPO + Lomustine Arm Only) 
Prior to implementation of protocol version 7, for patients randomized to the PVSRIPO 
with lomustine arm, lomustine was dispensed as an oral therapy at 110 mg/m2 one time 
only 8 weeks after PVSRIPO infusion. If a subject was on bevacizumab (had been 
treated with bevacizumab in the time since PVSRIPO infusion), the lomustine dose was 
dispensed as an oral therapy at 90 mg/m2 one time only 8 weeks after PVSRIPO 
infusion. The dose of lomustine was calculated by the subject’s weight at the week 8 
study visit. Lomustine was self-administered by the subject. The study team asked the 
subject for the exact date they took the lomustine and dosage amount taken for 
documentation. 
9.1.6 Safety Considerations 
Lomustine safety: Although not applicable after protocol version 7, the major toxicity of 
lomustine is delayed bone marrow suppression, so blood counts were monitored at a 
frequency determined by the treating physician. Given that lomustine was administered 
only once and pulmonary toxicity with lomustine is a cumulative toxicity, a pulmonary 
function test in the PVSRIPO + lomustine arm was not be required. Long-term use of 
nitrosoureas has been reported to be possibly associated with the development of 
secondary malignancies, which should be prevented by the use of a single cycle of 


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lomustine. Liver and renal function tests were to be monitored periodically, per standard 
of care practices. 
 
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. 
 
Anesthesia: Patients undergoing general anesthesia may be subjected to associated 
risks including pneumothorax, pneumonia, airway injury, hypotension, myocardial 
infarction, stroke, hepatic and renal injury and death. 
 
Poliomyelitis: PVSRIPO has been tested in NHPs according to the WHO standardized 
monkey neurovirulence tests. These tests revealed the absence of neuropathogenic 
properties, evident as failure to induce symptoms of poliomyelitis in NHPs after 
intracerebral inoculation of virus. However, PVSRIPO is a replication-competent viral 
agent that, in principle, retains the potential to cause motor neuron damage. Possible 
complications include transient or permanent mono- or paraparesis, paralysis, and life-
threatening respiratory insufficiency. 
 
Virus Recombination and Mutation: PVSRIPO retains the ability to alter its genome 
during replication upon administration to patients. Various mechanisms are known to 
lead to genetic adaptation, including spontaneous mutagenesis and recombination that 
may give rise to viral progeny with changed properties. Empirical studies in tissue 
culture and laboratory animals demonstrated that prolonged passaging in glioblastoma 
cells does not select for genetic changes in viral progeny. However, the occurrence of 
such events cannot be categorically excluded in patients receiving intracerebral 
PVSRIPO. Genetic changes may cause an altered phenotype of PVSRIPO, including 
adaptation to improved virus replication in the normal CNS. 
 
Long-Term Sequelae of Virus Injection: PVSRIPO does not encode foreign genetic 
material; PVs are unable to insert viral genetic material in the host genome and PVs are 
incapable of inducing latent or chronic CNS infection. Therefore, PVSRIPO is unable to 
induce long-term expression of foreign polypeptides or long-term persistence. Thus, 
there are no long-term neurologic consequences to intracerebral PVSRIPO 
administration in study subjects. For these reasons, no specific measures to analyze the 
potential for persistence of virus replication in the CNS of long-term survivors are 
indicated. 
 
Gastrointestinal Infection and Virus Excretion: After oral uptake, PV replicates in the 
gastrointestinal tract and is excreted by infected individuals with stool. Gastrointestinal 


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viral replication usually is asymptomatic but may cause mild symptoms of 
gastrointestinal discomfort. Excretion of PVSRIPO with stool does not occur after 
intracerebral inoculation in immunized/boosted patients. This is based on thorough 
testing in 61 patients in the first-in-human phase 1 trial and much historical evidence 
from investigations in NHPs. 
Cerebral Edema and Increased Intracranial Pressure: Cerebral edema may 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. Symptoms of neurologic 
dysfunction due to cerebral edema may include, but are not limited to, seizures, severe 
headache, confusion, lethargy, unresponsiveness, coma, or focal neurological deficits. 
Patients will be monitored throughout the course of the study and upon any signs or 
symptoms of cerebral edema, may have their steroid doses increased or receive 
treatment with an antiangiogenic agent (according to Special Considerations below), 
osmotic diuretic, or 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, preoperative neurological 
impairment, and post-operative course prior to virus administration. The risks will be 
discussed with the subject and the subject’s family. Guidelines for reporting serious 
adverse events (SAEs) related to neurologic dysfunction due to cerebral edema are 
details in Section 12.8.4.  
Special Consideration: In the event a patient demonstrates neurologic or radiographic 
signs suggestive of a localized inflammatory reaction secondary to the immune 
response triggered by PVSRIPO that requires a dose of dexamethasone above 4 mg a 
day after the first 4 weeks post-PVSRIPO infusion, every effort should be made not to 
increase the dose of dexamethasone further. Instead, patients should be treated with 
bevacizumab 7.5 mg/kg IV every 3 weeks. If a subject requires planned treatment with 
bevacizumab > 7.5 mg/kg every 3 weeks, they will be considered off study and enter the 
follow-up phase. Neuroimaging (MRI) will be performed according to protocol schedule, 
and at that time, it will be assessed whether further treatment with bevacizumab is 
needed to control the cerebral inflammation. It is recommended that bevacizumab 
treatment start no earlier than 4 weeks after PVSRIPO infusion, in consideration of 
bleeding/wound healing in keeping with the package insert, but is at the 
investigator’s/treating center’s discretion/standard procedures following biopsy. 
Bevacizumab will not be provided by the study. Every attempt should be made to 
discontinue dexamethasone. 


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In initial phase 1 and 2 clinical trials, four potential bevacizumab-associated adverse 
events (AEs) were identified: hypertension, proteinuria, thromboembolic events, and 
hemorrhage. Additional completed phase 2 and phase 3 studies of bevacizumab, as 
well as spontaneous reports have further defined the safety profile of this agent. 
Bevacizumab-associated AEs identified in phase 3 trials include congestive heart failure 
primarily in metastatic breast cancer, gastrointestinal perforations, wound-healing 
complications, and arterial thromboembolic events. These and other safety signals are 
described in further detail in the bevacizumab package insert. 
 
If there are AEs or other circumstances prohibiting the use of bevacizumab, 
corticosteroids or surgery, or other interventions deemed more appropriate for the 
patient by the treating physician, will be used, if needed, to treat any localized 
inflammatory reaction secondary to PVSRIPO. 
 
Risk of Infection: The intracerebral catheter placement and infusion may include the risk 
of infection. However, similar procedures including stereotactic biopsy and 
ventriculostomy placement are commonly used in the routine clinical care of patients 
with malignant brain tumors with a very low and acceptable rate of infection. In the most 
extreme situation, however, infection may lead to systemic bacterial/fungal sepsis and 
possibly death. The risk of infection will be minimized by performing catheter 
implantations in the Operating Room. Patients will be monitored throughout the course 
of the study for any signs and symptoms of infection. If an active infection is suspected, 
patients will be cultured and treated with appropriate antibiotics. 
 
Risk of Phlebotomy: Drawing blood or inserting an intravenous catheter into an arm vein 
may result in bruising or swelling in the area of the insertion, bleeding at the site of the 
needle puncture, light headedness, fainting and very rarely, local infection, which may 
be severe. These risks are reduced by the fact that the blood will be drawn by a 
qualified physician, nurse or phlebotomist (a professional trained to draw blood). 
 
Risks of MRIs: Risks and/or discomforts associated with MRI scans include anxiety 
produced from being in a tight, enclosed space (claustrophobia). In addition, the 
machine operates using a large and powerful magnet, which attracts certain metals. 
Therefore, people with these metals in their bodies (specifically pacemakers, infusion 
pumps, metal aneurysm clips, metal prostheses, joints, rods or plates) will be excluded 
from the study. Patients will also be checked to make sure that they do not bring any 
metal objects into the MRI facility. Dental fillings are less affected by the magnetic fields 
generated and are therefore permitted. Patients will be asked to let the physicians 
conducting this study know of any metal in their bodies other than dental fillings. 
 
Allergic Reactions to Contrast Agents: For MRI with contrast (considered standard of 
care for follow-up of rGBM patients), a contrast agent is administered through the vein, 
which requires the placement of an IV catheter. The catheter placement is similar to 
drawing blood except that the catheter remains in the vein during the time the agent is 
actively delivered. The risks of a blood draw and insertion of a catheter are similar. 
There have been a few, rare cases of allergies to the agent used in MRI contrast 


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enhanced scans. Patients with any current or history of anaphylactic reactions to 
gadolinium-based contrast agents will be excluded from the study. Patients with less 
severe allergies (ie, manageable with prophylaxis) should be pretreated with Tylenol® 
and Benadryl® prior to injection of the contrast agent, per the treating clinician. Prior to 
protocol version 8, in addition to the gadolinium (contrast agent) being given for MRI 
contrast, it was also co-infused with the study drug to assess infusion distribution. As 
noted previously, production of the contrast agent was discontinued by the 
manufacturer for non-safety reasons and will no longer be included in the infusate. This 
approach to gadolinium administration was not FDA approved. The potential risks of 
intracerebral infusion of gadolinium contrast agents  were not completely known but  
were believed to be small. Risks for infusion of gadolinium contrast agents intrathecally 
for procedures such as cisternography have been somewhat better studied, and were 
recently summarized by Selcuk et al (2009)37. Encephalopathy, coma and seizures 
have been reported as side effects in case reports of accidental administration of large 
amounts of gadolinium contrast agents intrathecally in humans36,38. When these 
contrast agents are used in an appropriately low dose, however, the risk of intrathecal 
administration appears reasonably low. No neurological sequelae attributable to the 
procedure were detected in a series of 85 patients37, in another series of 95 patients at 
a one year follow-up39, or in any of 51 patients after over 4 years of mean follow-up in 
another study40. No complication from the intracerebral infusion of gadolinium contrast 
agents was observed in the 61 patients treated in the phase 1 PVSRIPO clinical trial or 
this study, to date. Although these results cannot be extrapolated to the procedure 
proposed in the previous version of this protocol, they indicate that direct exposure of 
the brain to small amounts of gadolinium contrast agent was generally well tolerated. 
A rare but serious adverse reaction has been observed in patients that received a 
gadolinium-based contrast material during MRI examinations, a reaction called 
nephrogenic systemic fibrosis (NSF). Patients with kidney disease are at increased risk 
of developing NSF. NSF may cause skin thickening, joint pain and/or swelling. In rare 
cases NSF can lead to lung and heart problems and cause death. In addition, given 
new information of possible retention of gadolinium-based contrast agents, only MRIs 
absolutely necessary for the proper management of the subject’s condition will be 
obtained. 
Risks to Household Contacts of Study Subjects: Primate toxicology studies showed that 
intracerebral infusion of PVSRIPO does not lead to extraneural dissemination or 
replication and, hence, is not associated with virus shedding. Therefore, and because 
PV transmission occurs via the fecal-oral route, the likelihood of unintended exposure of 
patient household contacts is exceedingly low. If accidental exposure occurred, it would 
equal the risk of exposure to any type 1 Sabin vaccine virus or vaccine virus derivatives. 
Thus, in essence, exposure with PVSRIPO is equal to oral immunization with a safe 
version of type 1 Sabin. Since type 1 Sabin vaccine virus or vaccine virus derivatives 
have to be considered part of the human environment, exposure to PVSRIPO would not 
represent an added risk beyond the possibility for exposure that already exists. 
Unknown Risks: The overall risk classification of this research is unknown. 


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9.1.7 Concomitant Medications 
9.1.7.1 
Steroids 
Corticosteroids should be used at the lowest dose required to control symptoms of 
edema and mass effect, and discontinued, when/if possible. Use of corticosteroids 
should be recorded in the eCRF. Every effort should be made to keep the dose of 
steroids at or lower than an equivalent of 4 mg daily of dexamethasone. 
9.1.7.2 
Anticonvulsants 
Anticonvulsants drugs should be used or continued, if indicated. Use of such 
anticonvulsants should be recorded in the eCRF. 
9.1.7.3 
Growth Factors 
Routine use of growth factors (ie, granulocyte-colony-stimulating factor [G-CSF], 
granulocyte-macrophage colony-stimulating factor [GM-CSF], and erythropoietin) is not 
permitted. However, therapeutic use of G-CSF in patients with serious neutropenic 
conditions, such as sepsis, may be used at the discretion of the treating physician. Use 
of such growth factors should be recorded in the eCRF. 
9.1.7.4 
Anti-emetics 
The use of anti-emetics will be at the discretion of the treating physician. Use of anti-
emetics should be recorded in the eCRF. 
9.1.7.5 
Proton Pump Inhibitors 
The use of proton pump inhibitors (eg, rabeprazole, omeprazole, pantoprazole, 
lansoprazole or esomeprazole) is allowed on this study. 
9.1.7.6 
Febrile Neutropenia 
Febrile neutropenia should be managed according to the local institutional guidelines. 
Measures include laboratory testing, blood and urine cultures, and institution of broad 
spectrum antibiotics. 
9.1.7.7 
Pneumocystis jiroveci Pneumonia (PJP) Prophylaxis 










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PVSRIPO must be stored at less than or equal to -70°C. Once thawed, it is a clear 
colorless liquid with no evidence of particulates or foreign matter. Details on the supply, 
receipt, and storage of PVSRIPO will be outlined in the SAM. 
 
10.1.4 
Dispensing and Preparation 
 
For aliquot preparation, the agent will be thawed slowly on ice (4C) and kept at that 
temperature. Thawed vials of PVSRIPO are stable at 4°C for 48 hours. PVSRIPO 
contained in the clinically intended delivery apparatus (ie, ready for infusion) is stable at 
room temperature for 18 hours but should be used as soon as possible. The 
manufacturer will provide the study agent’s potency (as TCIDs) and will also supply the 
appropriate vehicle for aliquot preparation. Aliquot preparation will occur in each 
institution’s designated investigational pharmacy preparation center. All handling of the 
study agent will occur in a biosafety cabinet or a similarly contained environment. 
 
Any materials in contact with the study agent, eg syringes, vials, etc., will be disposed of 
as biological waste.  The final desired aliquot of the study agent infusate will be 
prepared at the intended volume, which is sufficient for priming the infusion tubing and 
for infusion. The capped infusion syringe containing infusate (and primed infusion tubing 
if primed in pharmacy) will be transported to the study site in a ‘ziplock’ bag placed in a 
portable cooler or similarly contained transport device with a frozen ice block/ice pack, 
in order to maintain a temperature of approximately 4°C.  There is no need to monitor 
the temperature during transport to the bedside. 
 
Details on dispensing and preparing study agent will be outlined in the Investigational 
Product–handling portion of the SAM. 
 
10.1.5 
Compliance and Accountability 
 
Drug accountability records will be maintained for all clinical trial supplies. All empty and 
partially used clinical trial supplies will be destroyed in accordance with institutional 
guidelines. Each site’s designated investigational pharmacy will maintain detailed 
documentation of the receipt and/or destruction of the study agent, which will then be 
provided to the Sponsor or designee. All materials coming in contact with the study 
agent, the syringe delivered from the investigational pharmacy, tubing, dressings or 
coverings used to protect the trepanation site, will be disposed of as biological waste in 
the treatment room. 
 
10.1.6 
Disposal and Destruction 
 
All surgical materials used in the procedure and (potentially) coming in contact with the 
study agent will be disposable. These materials will be disposed of as biological waste 








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b. Patients with known immunosuppressive disease or known human 
immunodeficiency virus infection 
c. Patients with unstable or severe intercurrent medical conditions such as severe 
heart disease (New York Heart Association Class 3 or 4) 
d. Patients with known lung (forced expiratory volume in the first second of 
expiration [FEV1] < 50%) disease or uncontrolled diabetes mellitus 
e. Patients with albumin allergy 
f. Patients with existing or history of anaphylactic reaction to gadolinium  
4. Patients with a previous history of neurological complications due to PV infection. 
5. Patients who have not recovered from the toxic effects of prior chemo- and/or 
radiation therapy. Guidelines for this recovery period are dependent upon the 
specific therapeutic agent being used. 
6. Patients may not have received tumor treating fields (≤ 1 week), chemotherapy or 
bevacizumab ≤ 4 weeks [except for nitrosourea and lomustine (≤ 6 weeks);  
metronomic dosed chemotherapy, such as daily temozolomide, etoposide or 
cyclophosphamide (≤ 1 week)] prior to starting the study drug. 
7. Patients may not have received immunotherapy ≤ 4 weeks prior to starting the study 
drug unless patients have recovered from side effects of such therapy. 
8. Patients may not be less than 12 weeks from radiation therapy of the brain, unless 
progressive disease outside of the radiation field or 2 progressive scans at least 4 
weeks apart or histopathologic confirmation. 
9. Prior to enrollment, has not completed all standard of care treatments, including 
surgical procedure and radiation therapy (at least 59Gy) 
a. If the MGMT promoter in their tumor is known to be unmethylated, patients 
are not mandated to have received chemotherapy prior to participating in 
this trial 
b. If the MGMT promoter in their tumor is known to be methylated or the 
MGMT promoter methylation status is unknown at time of screening, 
patients must have received at least one chemotherapy regimen prior to 
participating in this trial 
c. If enrolling at 2nd recurrence, must have failed treatments initiated at 1st 
recurrence 
10. Patients with neoplastic lesions in the brainstem, cerebellum, or spinal cord; 
radiological evidence of multiple areas of active (growing) disease (active multifocal 
disease); tumors with contrast-enhancing tumor component crossing the midline 
(crossing the corpus callosum); extensive subependymal disease (tumor touching 
subependymal space is allowed); or extensive leptomeningeal disease (tumor 
touching leptomeninges is allowed). 
11. Patients with undetectable anti-tetanus toxoid immunoglobulin G (IgG). 
12. Patients with known history of agammaglobulinemia. 
13. Patients on greater than 4 mg per day of dexamethasone within the 2 weeks prior to 
admission for PVSRIPO infusion. 
14. Patients with worsening steroid myopathy (history of gradual progression of bilateral 
proximal muscle weakness, and atrophy of proximal muscle groups). 




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• A serum test for lymphocyte subset quantitation (LSQ) and anti-tetanus toxoid 
IgG 
• Whole blood drawn (10-20 mL) for serum collection for determination of PV titer 
(the results of this screening PV titer must be known prior to the PVSRIPO 
infusion), whole blood (~4-6 ml) for isolation of buffy coat and other immunologic 
analysis (~76.5 mL) 
o NOTE: Blood draw for LSQ quantitation, PV titer and immune cell analysis 
will not be collected prior to any PVSRIPO retreatment(s) 
• As part of a smaller sub-study only at DUMC, subjects at this center may have an 
additional 6 ml of blood drawn prior to PVSRIPO infusion to explore 
inflammation-associated biomarkers, immune cell phenotype and innate and 
adaptive immune competence. 
o NOTE: Blood draw for participants in the DUMC sub-study will not be 
collected prior to PVSRIPO retreatment(s) 
• For newly enrolled subjects who have not received PVSRIPO under a previous 
version of the protocol, a stool sample will be obtained via the OMNIgene 
(OMNIgene®•GUT (OMR-200)) stool sample kit  
o The complete collection kit will be dispensed to the subject for the sample 
to be obtained prior to the subject receiving the PVSRIPO infusion. 
o The subject may return the pre-paid postage kit directly to the laboratory 
conducting the analyses. All instructions will be provided. 
o NOTE: Stool samples are not collected prior to PVSRIPO retreatment(s) 
 
Following this blood draw, the patient will receive a booster of inactivated PV vaccine (≥ 
1 week but ≤ 6 weeks of the initial PVSRIPO infusion; ≥ 1 week but ≤ 6 months of any 
PVSRIPO retreatments). 
 
The screening examination will take place within 14 days before catheter placement, but 
as close to biopsy as possible. Whenever possible, when confirming eligibility based on 
the study inclusion/exclusion criteria, the least invasive screening procedures (eg, KPS) 
should be performed first and the most invasive last. 
 
Pre-treatment evaluations within 14 days before catheter placement, but as close to 
biopsy as possible, to determine eligibility will include the following, unless otherwise 
indicated: 
• Clinical assessment (including medical history) and physical examination, 
including a neurologic assessment and KPS within 14 days of catheter 
placement 
• Laboratory Evaluations: 
o Complete blood count (CBC) with differential 
o Comprehensive metabolic panel (CMP) 
o Prothrombin time (PT) and activated partial thromboplastin time (aPTT) 
o Beta-human chorionic gonadotropin (HCG), if appropriate (within 14 days of 
catheter placement and 48 hours of PVSRIPO infusion) 
o Whole blood for immunologic analysis (~ 96.5 mL) 




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Day 1 post-infusion 
• Clinical assessment and physical examination, including a neurologic 
assessment and KPS, to be performed daily until discharged from the hospital 
(must be documented within 24h (± 4h) of actual discharge 
• CBC with differential 
• CMP 
• 3 ml of blood to explore inflammation-associated biomarkers/immunologic 
analysis (NOTE: collection on Day 1 or Day 2 post-infusion acceptable; 
Participants retreated with PVSRIPO will not have blood drawn for biomarker 
analyses) 
 
Week 1 (+/- 3 days) 
• Clinical assessment and physical examination, including a neurologic 
assessment and KPS 
• CBC with differential 
• CMP 
• Participants in the DUMC sub-study should have a 6ml blood draw to explore 
inflammation-associated biomarkers, immune cell phenotype and innate and 
adaptive immune competence 
o NOTE: Participants in DUMC sub-study retreated with PVSRIPO will not 
have additional blood drawn for biomarker analyses.  
 
Week 2 (+/- 1 week) 
• Clinical assessment and physical examination, including a neurologic 
assessment and KPS 
• CBC with differential 
• CMP 
• Whole blood (96.5 mL) for immunologic analysis 
o NOTE: Participants retreated with PVSRIPO will not have blood drawn for 
biomarker analyses 
 
Week 4 (+/- 1 week) 
• Clinical assessment and physical examination, including a neurologic 
assessment and KPS 
• MRI of the brain with gadolinium contrast 
• CBC with differential 
• CMP 
 
Week 8 (+/- 1 week) 
• Clinical assessment and physical examination, including a neurologic 
assessment and KPS 
• MRI of the brain with gadolinium contrast 
• CBC with differential 
• CMP 
• Whole blood (96.5 mL) for immunologic analysis 


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o NOTE: Participants retreated with PVSRIPO will not have blood drawn for 
biomarker analyses provided they are > 8 weeks out from initial PVSRIPO 
infusion 
• Beta-HCG, if appropriate and if randomized to the lomustine arm prior to protocol 
version 7 
o NOTE: Participants randomized to the lomustine arm that are retreated 
with PVSRIPO are not required to repeat the pregnancy test at 8 weeks. 
• Prior to protocol version 7, patients randomized to the lomustine cohort received 
a single oral dose (while on lomustine, additional CBCs and CMPs were obtained 
at a frequency determined by the treating physician). The lomustine dose may 
have been taken the day of the week 8 visit or 1 day after the visit. 
• A stool sample will be obtained via the OMNIgene®•GUT (OMR-200) kit. NOTE: 
for patients who already received PVSRIPO under a previous version of the 
protocol and for whom the Week 8 visit has passed, they will be provided with the 
OMNIgene®•GUT stool collection kit for their post-infusion stool sample at their 
next clinic visit. 
o NOTE: Participants retreated with PVSRIPO will not have stool collected 
for biomarker analyses provided they are > 8 weeks out from initial 
PVSRIPO infusion 
 
After protocol version 7, the Week 12 (+/- 1 week) visit and all protocol associated 
assessments associated with this visit outlined below have been removed and are not 
required, as they were primarily associated for comparisons between PVSRIPO with or 
without lomustine use. This includes: 
  
• Clinical assessment and physical examination, including a neurologic 
assessment and KPS 
• CBC with differential 
• CMP 
 
For patients randomized to the lomustine arm prior to protocol version 7, this visit was 4 
weeks post lomustine dose (+/-1 week). 
 
 
Weeks 16, 25, 34, 43, 52 (+/- 1 week) 
• Clinical assessment and physical examination, including a neurologic 
assessment and KPS 
• MRI of the brain with gadolinium contrast 
• CBC with differential 
• CMP 
 
After week 52, patients will follow-up at the discretion of the treating physician, receiving 
periodic MRIs, but will still be considered on study. 
 
Data obtained at each visit/phone call should be entered in the eCRF approximately 
every 1 to 2 months, in keeping with the patient’s follow-up until the patient is off study, 








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difficult. Therefore, an exploratory objective of this study is to describe radiographic 
imaging post-PVSRIPO treatment. In the phase 1 PVSRIPO clinical trial, an initial 
increase in the extent of FLAIR abnormalities could be observed after PVSRIPO, 
followed by a decrease in the extent of FLAIR abnormalities. 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. Depending on the size of the tumor, the changes could be observed up to 12 
months post-PVSRIPO infusion. The qualitative description of the changes observed in 
this trial will help to better characterize imaging following PVSRIPO infusion and refine 
imaging assessment criteria specific to PVSRIPO. 
 
Imaging based responses will be noted by the assessing clinician as well as 
independent central imaging reviewers, blinded to the patient outcome, in keeping with 
an imaging charter to be finalized prior to image assessment.  
 
In addition, routine teleconferences with participating investigators at each site will be 
conducted by the Sponsor or designee in order to discuss radiographic issues, as well 
as enrollment, subject updates, and study conduct. Except in case of eminent life-
threatening emergency, consult with the study-designated neurooncologist(s)/ISC prior 
to administration of non-protocol-specified treatments and/or surgical resection, if 
radiographic progression is suspected. 
 
For lesion measurement, the axial post contrast T1 slice where the enhancing lesion is 
at the largest on the baseline screening MRI (pre-infusion MRI), should be identified as 
the “target lesion.” Please note that as per RANO criteria for determination of target 
lesion, the enhancing lesion should measure at least 1 x 1 cm and resection cavity or 
cystic area should not be included in the baseline tumor volume measurement. Over 7 
years of experience with PVSRIPO have demonstrated that on follow-up imaging, an 
initial change in configuration of the target lesion is expected, often with increase in size 
of the lesion; this is due to the process of intratumoral administration itself and the 
immunotherapy effect of PVSRIPO, which often triggers microcystic degeneration of the 
previously densely enhancing area, as well as an extension of an enhancing immune 
reaction into previously non-enhancing infiltrative disease. Such changes will not be 
described as progressive disease, but as “immunoprogression” (a term coined for 
PVSRIPO, to distinguish from pseudoprogression, which is often reserved to imaging 
changes occurring after radiation therapy). This is often followed months later by a 
tumor retraction.  
 
Complete response and partial response of the treated lesion will be defined using the 
same criteria as in iRANO. However, in the case a patient is initiated on protocol 
specified dosage of bevacizumab for management of symptoms of immunoprogression 
and imaging demonstrates a complete or partial response of the target lesion while on 
bevacizumab, this response must be maintained for at least 8 weeks after coming off 
low dose bevacizumab to be considered a treatment related radiographic response.  
 


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It is to note that with time, a number of patients develop a cystic/necrotic area with a thin 
rim of residual enhancement the same size (replacing the target lesion) or sometimes 
slightly larger than the previously densely enhancing target lesion, this should be 
labeled as stable disease.  
Given the radiographic changes post PVSRIPO making it impossible to properly identify 
true disease progression based solely on imaging criteria, per protocol, patients should 
not be taken off study for progressive disease based solely on imaging criteria. As per 
protocol, patients can come off study due to progression only once it has been shown 
that they are not improving clinically with protocol allowed dose of bevacizumab only 
and therapy in addition to low dose bevacizumab must be added. 
12.7.4 
Laboratory Evaluations 
The timing of laboratory assessments that will be obtained during the course of 
the study is given above in Table 1. A list of each evaluation is below. 
•
CBC with differential
•
CMP
•
PT, aPTT
•
Beta-HCG, if applicable, within 48 hours prior to receiving the PVSRIPO infusion 
and for patients who received lomustine prior to protocol version 7, prior to the 
cycle of lomustine (lomustine arm)
•
Immunologic/Genetic/Gut Microbiome testing: may include tests noted in Section 
14.7.
12.7.5 
Correlative Assessments 
•
Anti-tetanus toxoid IgG titer within 6 weeks prior to treatment will be obtained by 
each institution and recorded in the eCRF.
•
The screening eligibility anti-PV titer results will be sent back to the sites for entry 
into their eCRF by the sponsor-designated laboratory.
•
LSQ (NOTE: Not required prior to PVSRIPO retreatment)
•
Anti-tetanus toxoid IgG
•
Prior to initial PVSRIPO infusion, a 96.5 mL sample of whole blood for immunologic 
assays and PV titer (at screening only) will be collected according to Section 12.3. 
From these samples, immune signatures may be identified using patient peripheral 
blood mononuclear cells to 1) track longitudinally with clinical outcomes in 
PVSRIPO-treated patients to determine the precise mechanism responsible for the 
therapeutic effects, and 2) predict which patients will derive the greatest benefit from 
PVSRIPO therapy based on their baseline immune profiles.
•
At screening for initial PVSRIPO infusion only, an additional 4-6 ml of whole blood 
will be obtained for isolation and storage of the buffy coat for future molecular




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• 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 or conditions present 
or detected at the start of the study that do not worsen. 
 
Adverse events related to the non-standard of care screening procedures (eg, polio 
vaccination booster) and biopsy/catheter placement procedure will be reported (non-
treatment emergent adverse events). Treatment emergent adverse events will be noted 
from the time of infusion through the time the subject comes off study (as defined in 
Section 9.5), all AEs must be recorded in the subject’s medical record and AEs case 
report form. Subjects will be followed for SAEs for 30 days after coming off study. 
 
AEs will be assessed according to the CTCAE (Common Terminology Criteria for 
Adverse Events) version 4.03. 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). 
 
Attribution of AEs will be indicated as follows: 
• Definite: The AE is clearly related to the study drug(s) 
• 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) 
 
Attribution of AEs will be determined for each study intervention individually (catheter 
placement, PVSRIPO, lomustine (only for patients randomized to this arm prior to 
protocol version 7), bevacizumab, and corticosteroids). 
 
12.8.1 
AEs of Special Interest 
 
See section 9.1.6 for management of anticipated AEs. 
 
12.8.2 
Reporting of AEs 
 
Any AE occurrence (spontaneously volunteered and enquired for, as well as observed 
AEs) during the study must be documented in the patient’s medical records in 
accordance with the investigator’s normal clinical practice and on the AE page of the 
eCRF. SAEs that occur during the study must be documented in the patient’s medical 
record, on the AE eCRF, and on the SAE form. 
 
The investigator should attempt to establish a diagnosis of the event based on the 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should 
be documented as the AE (and SAE if serious) and not the individual signs/symptoms. 
 


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If an abnormal laboratory finding or other abnormal assessment meets the definition of 
an AE, then the AE eCRF page must be completed as appropriate. In addition, if the 
abnormal assessment meets the criteria for being serious, the SAE form must also be 
completed. A diagnosis, if known, or clinical signs or symptoms if the diagnosis is 
unknown, rather than the clinically significant laboratory finding or abnormal 
assessment, should be used to complete the AE/SAE page. If no diagnosis is known 
and clinical signs or symptoms are not present, then the abnormal finding should be 
recorded. Only laboratory results considered clinically significant by the clinical 
investigator that are not part of or supportive of a diagnosis should be reported as an 
AE. If an SAE report is completed, pertinent laboratory data should be recorded on the 
SAE form, preferably with baseline values and copies of laboratory reports. 
 
Reporting of any SAEs to applicable regulatory authorities will be the responsibility of 
the Sponsor or designee in compliance with local regulations. The SAE page should be 
completed as thoroughly as possible and signed by the investigator before transmittal to 
the assigned safety representative. It is very important that the investigator provide an 
assessment of the causal relationship between the event and the study drug(s) at the 
time of the initial report, as this will be useful for submissions to regulatory authorities. 
 
A database of all AEs (not just those considered related to the study drug(s)) will be 
maintained in 21 CFR Part 11 compliant database. The event will be categorized by 
organ system, relationship to treatment, its grade of severity, and resolution. The 
Sponsor/designee, along with an independent DSMB, will periodically review the 
collective AEs with the intention of identifying any trends or patterns in toxicity. If any 
such trends are identified, depending on their severity and frequency, a protocol 
amendment will be considered. 
 
12.8.3 
Serious Adverse Events (SAEs) 
 
An AE is considered “serious” if it is one of the following outcomes: 
• Fatal 
• Life-threatening 
• Constitutes a congenital anomaly or birth defect 
• A medically significant condition (defined as an event that compromises subject 
safety or may require medical or surgical intervention to prevent one of the three 
outcomes above). 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant incapacity or substantial disruption to conduct 
normal life functions. 
12.8.4 
Reporting of SAEs 
 
SAEs must be reported by the PI to the Sponsor or designee within 24 hours of discovery 
while patients are on study and for 30 days after patients are taken off study.  
 


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The PI 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 PI before transmittal to the 
Sponsor or designee. The PI should not wait to for additional information to fully document 
the related SAE before notification, although additional information may be requested.  
 
Instances of death not due to disease progression, 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 PI at any time after cessation of study drug(s) and linked by the PI 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. 
 
Contact information for processing SAEs can be found in the study administration manual 
(SAM). 
 
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. 
The Investigator (or Sponsor where required) must report any SUSARs to the IRB 
according to the Institution’s regulations. 
 
REPORTING OF SERIOUS ADVERSE EVENTS RELATED TO CEREBRAL EDEMA 
• 
Events related to cerebral edema that meet criteria for a serious adverse event 
(SAE) should be reported as described in the protocol and study procedures (ie, 
within 24h of learning of the event). Investigators who have concerns about the 
protocol-specified medical management of cerebral edema, or the determination 
of possible progressive disease, should contact the study designated neuro-
oncologist to discuss the case as noted. 
• 
When reporting the SAE, describe the following in the narrative description of 
the event: 
• Specific signs and symptoms of edema, such as seizures, headache, 
confusion, lethargy, unresponsiveness, coma, or focal neurologic deficits 
(eg, pyramidal tract syndrome, hemiparesis) 
• In addition, any specific signs or symptoms considered to be out of proportion for 
the extent of edema may be reported as additional SAEs, if indicated.   
• 
The narrative description should include the following: 
o Time to onset following PVSRIPO infusion 
o Maximum severity of signs and symptoms 
o Treatment(s) undertaken 
o Time to resolution as the information becomes available 
 
 
12.8.5 
Toxicity Monitoring 
 


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Patients will be monitored for toxicity while on study. AEs will be categorized and 
graded in accordance with the NCI CTCAE (Version 4.03). Unacceptable AEs, as 
defined in Section 12.8.6, will be identified during this period of toxicity monitoring. 
 
12.8.6 
Definition of Unacceptable Adverse Event (ie, Adverse Events 
of Special Interest) 
 
An unacceptable AE (ie, adverse event of special interest; AESI) is any grade 3 or 
grade 4 toxicity considered related (possibly, probably or definitely) to a protocol 
treatment (includes surgical biopsy/infusion procedure, PVSRIPO, lomustine (for 
patients randomized to this arm prior to protocol version 7), bevacizumab, 
corticosteroids) that is not reversible (ie, does not improve to ≤ grade 2 with exception of 
neurologic events, which must only improve from highest grade level to next lower 
grade level) within 2 weeks. This includes any treatment-related life-threatening event or 
any treatment-related death. Any grade 2 or higher serious autoimmune toxicities—
particularly those affecting vital organs (eg, cardiac, renal, CNS)—will also be 
considered unacceptable AEs if they occur within 2 weeks of any protocol treatment, 
whether the AE requires intervention.  
 
Exceptions to unacceptable AEs noted above are as follows, with or without supportive 
treatment: 
 
• Events associated with the biopsy procedure/catheter placement: seizures or 
hemorrhages occurring during anesthesia or the biopsy/catheter insertion prior to 
administration of the agent if grade 2 or lower (grade 3 or higher surgical 
complication from insertion of catheter is considered an unacceptable AE). 
• Seizures: Due to the nature of the disease under investigation in this protocol, 
patients may have preexisting seizures or be susceptible to new seizures as a 
result of the underlying disease process. Although seizures may be defined as 
grade 3 or 4 toxicities under NCI Common Terminology Criteria (CTC), and will 
be reported as such in this protocol, seizures will not be considered an 
unacceptable AE if, in the opinion of the institutional PI, they have not increased 
in frequency or can be attributed to another recognized cause of increasing 
seizure frequency such as subtherapeutic anticonvulsant levels or biopsy-proven 
tumor progression. 
• New neurologic deficits: Due to the nature of the disease under investigation in 
this protocol, patients may develop new neurologic deficits as a result of tumor 
invasion or inflammation. A new neurologic deficit or worsening of a known 
neurologic deficit, which resolves (ie, returns to baseline) within 2 weeks after 
initiation of medical therapy (eg, corticosteroids or bevacizumab at 7.5 mg/kg IV 
every 3 weeks) will not be considered an unacceptable AE. 
• Thromboembolism: Due to the high incidence of deep vein thrombosis (DVT) in 
this patient population, patients may have undiagnosed preexisting DVTs or be 
susceptible to the development of DVTs due to the underlying disease process. 
Although DVT may be defined as a grade 3 or 4 toxicity under NCI CTC, and will 


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be reported as such in this protocol, DVT will not be considered an unacceptable 
AE in this protocol. 
• Syndrome of inappropriate antidiuretic hormone (SIADH): Due to the high 
incidence of SIADH in this patient population, patients may be susceptible to the 
development of SIADH due to the underlying disease process. Although SIADH 
may be defined as grade 3 toxicity under NCI CTC, and will be reported as such 
in this protocol, SIADH will not be considered an unacceptable AE in this protocol 
unless it is refractory to medical management. 
• Muscle weakness and weight gain: Due to the high incidence of generalized 
muscle weakness (ie, steroid myopathy) and weight gain in patients taking 
steroids in this patient population, patients may be susceptible to the 
development of generalized muscle weakness or weight gain, which is due to 
steroids alone. Although generalized muscle weakness may be defined as grade 
3 or grade 4 toxicity and weight gain ≥ 20% may be defined as grade 3 toxicity 
under NCI CTC, and will be reported as such in this protocol, generalized muscle 
weakness or weight gain will not be considered an unacceptable AE in this 
protocol if the patient has required steroids greater than the physiologic doses in 
the interval between the immunization and the development of the toxicity. 
• Tumor progression: Due to the nature of the disease under investigation in this 
protocol, patients may have an increase in preexisting neurologic deficits or have 
an onset of new neurologic deficits due to tumor progression. Although such 
neurologic deficits may be defined as unacceptable AEs under NCI CTC, and will 
be reported as such in this protocol, these clinical changes are not an 
unexpected phenomenon in this disease in the setting of tumor growth. As a 
result, neurologic deficits will not be considered an unacceptable AE if 
unequivocal tumor progression can be documented radiographically or 
histologically. 
 
12.8.6.1 
Guidelines for Monitoring Unacceptable Adverse Events 
 
Given that both long- and short-term toxicities are of interest in this study, it is not 
feasible to suspend accrual while toxicity is assessed, as is often done in phase 1 trials. 
If the following criteria are satisfied or there are other reasons for concern about the 
safety of patient treatment (eg, treatment-related toxic death; concerns are raised by the 
Data and Safety Monitoring Board [DSMB] or the Sponsor or their designee), accrual 
will be suspended and data will be carefully reviewed to determine if accrual should be 
permanently terminated or the protocol modified. These guidelines have not been 
adjusted for differential length of follow-up of accrued patients. 
 
Prior to protocol v7, each treatment group will be monitored independently of the other 
by the DSMB. However, if there are reasons for accrual suspension in either arm, 
accrual to both arms will be suspended pending a comprehensive review of patient 
experiences. 
 
Tabulated below are the conditions under which accrual will be temporarily suspended 
and data carefully reviewed to determine the appropriate action, including permanent 


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study termination, continuation with patient accrual after appropriate amendment, or 
continuation with patient accrual with no modification of the protocol. Accrual will also be 
suspended whenever a death occurs that is possibly, probably, or definitely related to 
protocol treatment. 
 
Table 3. Accrual of Unacceptable Adverse Events 
Number of Patients Accrued Within 
a Group 
Number of Patients with Unacceptable Adverse 
Events Within Group Requiring Accrual 
Suspension 
2-5 
> 2 
6-8 
> 3 
9-12 
> 4 
13-17 
> 5 
18-25 
> 6 
> 25 
> 7 
 
These guidelines have not been adjusted for differential length of follow-up of accrued 
patients. The probability of accrual suspension as a function of the true unacceptable 
toxicity rate is tabulated below based on simulation studies. These statistics were 
generated assuming toxicity outcome was known at the time of accrual and ignored 
issues such as time to toxicity, accrual rate, and length of follow-up. 
 
Table 4. Probability of Unacceptable Adverse Events 
Underlying Unacceptable 
Adverse Event Rate 
Probability of Accrual 
Suspension 
Expected Number of 
Accrued Patients 
0.05 
0.0002 
30.9 
0.10 
0.0027 
30.5 
0.15 
0.12 
29.3 
0.20 
0.33 
26.6 
0.25 
0.58 
23.0 
0.30 
0.80 
18.8 
0.35 
0.92 
15.0 
0.40 
0.97 
12.3 
 
 
In addition to the Sponsor, their designee, and the medical monitor, the FDA and/or the 
DSMB for this study may be part of this decision-making in the event that there are 
unacceptable toxicities or inflammatory issues. 
 
12.8.7 
Notification of Pregnancy 
 
Because all patients are required to have a boost immunization of trivalent inactivated 
IPOL™, there should be no risk of transmission of a mother to her fetus after receiving 


























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PVSRIPO and the date of death. If the patient remained alive at the date of last 
follow-up, survival time was censored at that date. 
 
Table 5. Characteristics of the Patients within the Historical Control Group 
Patient Characteristics 
N 
% 
All 
96 
100.0 
Gender 
 
 
Female 
36 
37.5 
Male 
60 
62.5 
Diagnosis 
 
 
GBM 
96 
100.0 
Age when first eligible for PVSRIPO, mean (SD) 
55.5 
(11.5) 
Age when first eligible for PVSRIPO, median (range) 
55 
(23-77) 
Maximal resection/surgical procedure at GBM diagnosisa 
 
 
Gross Total Resection (GRT) 
63 
65.6 
Subtotal Resection (STR) 
23 
24.0 
Biopsy 
10 
10.4 
Number of prior progressions until first eligible for PVSRIPO 
 
 
1 
85 
88.5 
2 
11 
11.5 
KPS when first eligible for PVSRIPO 
 
 
100 
8 
8.3 
90 
61 
63.5 
85 
1 
1.0 
80 
24 
25.0 
70 
2 
2.1 
Bevacizumab prior to when first eligible for PVSRIPO 
 
 
No 
49 
51.0 
Yes 
47 
49.0 
Bevacizumab failure prior to when first eligible for PVSRIPO 
 
 
No 
60 
62.5 
Yes 
36 
37.5 
Vital status 
 
 
Alive 
1 
1.0 
Dead 
95 
99.0 
GBM = glioblastoma; KPS = Karnofsky performance status; PVSRIPO = polio/rhinovirus recombinant; SD = standard deviation; 
a 2 patients with a maximal resection of "STR/GTR?" were coded as a STR, and 1 patient with "GTR to main tumor, STR to satellite 
lesion" was coded as a GTR. 
 
 
 
 
 


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SAP_001.pdf: 
Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
 
 
 
 
 
 
 
S T A TI S TI C A L A N A L Y SI S P L A N  
 
 
St u d y Title:  
A M ultice nter P hase 2 St u d y of O nc ol ytic P oli o/ R hi n o vir us 
Rec o m bi na nt ( lera p olt ure v, f or merl y k n o w n as P V S RI P O) i n 
Rec urre nt W H O Gra de I V Mali g na nt Gli o ma Pa tie nts 
 
 
P h ase:  
II 
 
 
Pr ot oc ol N o.:  
Pr o 0 0 0 7 7 0 2 4  
 
 
Pr ot oc ol D ate (s): 
Versi o n 8. 0: 0 7 Fe br uar y 2 0 2 0  
 
 
 
 
 
 
 
 
A n al ysis Pl a n Versi o n a n d 
D ate : 
Fi nal Versi o n 2. 0 : 2 7 J ul y 2 0 2 2  
 
 
Pre p are d B y:  
Kristie K usi ba b , M Bi ostat 
P har P oi nt Researc h, I nc.  
5 0 0 3 S. Mia mi B lv d.  
S uite 1 0 0  
D ur ha m, N C 2 7 7 0 3  
 
 
 
Pre p are d F or:  
Istari O nc ol o g y I nc. 
4 3 0 Da vis Dri ve , S uite 5 6 0 
M orris ville , N C 2 7 5 6 0  
 
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y I N F O R M A TI O N


Istari O nc ol o g y I nc. 
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S T A TI S TI C A L A N A L Y SI S P L A N R E VI E W A N D A P P R O V A L  
 
T his Statistical A nal ysis Pla n  has bee n pre pare d i n acc or da nce wit h tea m re vie wers’ s pecificati o ns.   
 
Pre pare d b y:  
 
 
 
 
 
Kristie K usi ba b, M Bi ostat  
Se ni or Bi ostatisticia n  
P har P oi nt Researc h, I nc.  
  
Date  
 
Re vie w:  
 
 
 
 
 
 
 
Zac k Sc ott, M S  
Se ni or Ma na ger , Bi ostatistics 
P har P oi nt Researc h, I nc.  
  
Date  
 
 
 
 
 
 
 
 
Garrett Nic h ols , M D, M S  
C hief Me dical Officer  
Istari O nc ol o g y I nc. 
  
Date  
J u l - 2 9 - 2 0 2 2  |  1 0 : 3 0  P D T
J u l - 2 9 - 2 0 2 2  |  1 3 : 3 5  E D T
J u l - 2 9 - 2 0 2 2  |  1 5 : 0 2  E D T


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T A B L E O F C O N T E N T S  
S T A TI S TI C A L A N A L Y SI S P L A N R E VI E W A N D A P P R O V A L  .............................................. 2  
1.  
I N T R O D U C TI O N .................................................................................................................... 5  
1. 1.   
S T U D Y O V E R VI E W  .......................................................................................................... 5  
1. 2.   
S C H E D U L E O F E V E N T S  .................................................................................................. 6  
1. 3.   
G L O S S A R Y O F A B B R E VI A TI O N S  .............................................................................. 1 3  
2.  
O B J E C TI V E S  ......................................................................................................................... 1 5  
3.  
G E N E R A L S T A TI S TI C A L C O N SI D E R A TI O N S  ............................................................. 1 6  
3. 1.   
S A M P L E SI Z E A N D P O W E R  ......................................................................................... 1 6  
3. 2.   
H A N D LI N G O F D A T A  .................................................................................................... 1 6  
3. 2. 1.  Str at a a n d C o v ari ates  ................................................................................................... 1 6  
3. 2. 2.  M ulti ple Testi n g a n d C o m p aris o ns  .............................................................................. 1 6  
3. 2. 3.  Missi n g D at a a n d O utliers  ............................................................................................ 1 6  
3. 2. 4.  Prese nt ati o ns b y St u d y Visit  ......................................................................................... 1 8  
3. 2. 5.  Prese nt ati o ns b y W orse C ase  ....................................................................................... 1 8  
3. 2. 6.  Defi niti o ns a n d Ter mi n ol o g y  ........................................................................................ 1 8  
3. 3.   
TI MI N G O F A N A L Y S E S  ................................................................................................. 2 1  
4.  
A N A L Y SI S P O P U L A TI O N S  ................................................................................................ 2 2  
4. 1.   
F U L L  A N A L Y SI S S E T  .................................................................................................... 2 2  
4. 2.   
S A F E T Y S E T  ..................................................................................................................... 2 2  
5.  
S T A TI S TI C A L M E T H O D S  .................................................................................................. 2 2  
5. 1.   
P A R TI CI P A N T DI S P O SI TI O N, D E M O G R A P HI C A N D B A S E LI N E 
C H A R A C T E RI S TI C S  ................................................................................................................... 2 3  
5. 2.   
DI S E A S E C H A R A C T E RI S TI C S  .................................................................................... 2 3  
5. 3.   
C O N C O MI T A N T M E DI C A T I O N S ................................................................................ 2 3  
5. 4.   
B R AI N S U R G E R Y, R A DI O T H E R A P Y A N D S Y S T E MI C T H E R A P Y  ..................... 2 4  


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5. 5.   
TI S S U E BI O M A R K E R S  .................................................................................................. 2 4  
5. 6.   
E X P O S U R E  ....................................................................................................................... 2 5  
5. 7.   
E F FI C A C Y  ......................................................................................................................... 2 5  
5. 7. 1.  Pri m ar y Effic ac y E n d p oi nts  ......................................................................................... 2 5  
5. 7. 2.  Pri m ar y Effic ac y A n al ysis  ............................................................................................ 2 6  
5. 7. 3.  Sec o n d ar y Effic ac y E n d p oi nts  ..................................................................................... 2 6  
5. 7. 4.  Sec o n d ar y Effic ac y A n al ysis  ......................................................................................... 2 6  
5. 8.   
S A F E T Y  ............................................................................................................................. 2 6  
5. 8. 1.  A d verse E ve nts  .............................................................................................................. 2 6  
5. 8. 2.  Cli nic al L a b or at or y Assess me nts  ................................................................................. 2 7  
5. 8. 3.  Vit al Si g ns  ...................................................................................................................... 2 8  
5. 8. 4.  K P S  ................................................................................................................................. 2 8  
6.  
P R O T O C O L D E VI A TI O N S  ................................................................................................. 2 8  
7.  
C H A N G E S I N T H E P L A N N E D A N A L Y S E S  ..................................................................... 2 8  
8.  
R E VI SI O N HI S T O R Y  ........................................................................................................... 2 9  
9.  
R E F E R E N C E S  ....................................................................................................................... 2 9  
1 0.  P R O G R A M MI N G C O N V E N TI O N S  ................................................................................... 3 0  
1 1.  P R O P O S E D T A B L E S, LI S TI N G S, A N D FI G U R E S  ......................................................... 3 2  
S U M M A R Y T A B L E S  .................................................................................................................... 3 2  
S U M M A R Y FI G U R E S  .................................................................................................................. 3 3  
D A T A LI S TI N G S  ........................................................................................................................... 3 3  
 


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1.   
IN T R O D U C TI O N  
T his d oc u me nt descri bes t he statistical met h o ds a n d data prese ntati o ns t o be use d i n t he pla n ne d 
data s u m mar y a n d a nal ysis of data fr o m Pr ot oc ol Pr o 0 0 0 7 7 0 2 4. Bac k gr o u n d i nf or mati o n is 
pr o vi de d f or t he o verall st u d y desi g n a n d o bjecti ves.  T he rea der is refe rre d t o t he st u d y pr ot oc ol 
a n d case re p ort f or ms ( C R Fs) f or details of st u d y c o n d uct a n d data c ollecti o n . 
1. 1.   
S T U D Y O V E R VI E W  
T his is a ra n d o mize d, m ultice nter, P hase 2 st u d y of t he safet y a n d efficac y of lera p olt ure v 
(f or merl y k n ow n as P V S RI P O) i n partici pa nt s wit h rec urre nt W orl d Healt h Or ga nizati o n ( W H O) 
gra de I V mali g na nt gli o ma. Lera p olt ure v is a rec o m bi na nt r hi n o vir us/ p oli o vir us ( P V) c hi mera 
a d mi nistere d b y i ntrat u m oral i njecti o n. A p pr o xi matel y 1 2 2 partici pa nt s will recei ve lera p olt ure v 
i ntrat u m orall y via c o n vecti o n e n ha nce d deli ver y ( C E D). Pri or t o pr ot oc ol versi o n 7, partici pa nt s 
were ra n d o mize d t o recei ve lera p olt ure v al o ne or lera p olt ure v f oll o we d b y l o m usti ne at wee k 8 -
p ost -i nf usi o n, w hic h was stratifie d b y ce nter. Fr o m pr ot oc ol versi o n 7 a n d be y o n d, ra n d o mizati o n 
t o t he lera p olt ure v + l o m usti ne ar m was disc o nti n ue d a n d partici pa nt s are t o be e nr olle d o nl y o n t he 
lera p olt ure v m o n ot hera p y ar m.  
 
Retreat me nt wit h lera p olt ure v is all o we d u p o n pr o gressi o n or rec urre nce of t u m or  i n partici pa nt s 
w h o are ≥ 1 2 m o nt hs o ut fr o m t he i nitial a n d s u bse q ue nt lera p olt ure v i nf usi o ns. I n or der t o q ualif y, 
t he retreat me nt eli gi bilit y criteria liste d i n Secti o n 9. 2. 1 of t he pr ot oc ol m ust be met. All cases f or 
c o nsi derati o n of lera p olt ure v retr eat me nt are t o be disc usse d wit h t he st u d y desi g nate d 
ne ur o o nc ol o gist/I n vesti gat or Steeri n g C o m mittee (I S C) f or a p pr o val pri or t o pr ocee di n g.  
 
Partici pa nt s will recei ve lera p olt ure v o n Da y 0 ( St u d y Da y 1) d uri n g t he I nf usi o n Peri o d. St u d y 
tests a n d pr oce d ures will be c ollecte d p ost-i nf usi o n ( F oll o w-u p Peri o d) o n Da y 1 a n d Wee k 1, 2, 4, 
8, 1 6 + e ver y 9 wee ks u ntil Wee k 5 2. After Wee k 5 2, partici pa nt s will f oll o w-u p at t he discreti o n 
of t he treati n g p h ysicia n, recei vi n g  peri o dic ma g netic res o na nce i ma gi n g ( M RIs), b ut will still be 
c o nsi dere d o n st u d y. W hile partici pa nt s are o n st u d y, t heir mali g na nt gli o ma ma y n ot be treate d 
wit h a n y m o dalit y f or ca ncer ot her t ha n lera p olt ure v or a si n gle d ose of l o m usti ne (f or t h ose 
ra nd o mize d t o t he l o m usti ne ar m pri or t o pr ot oc ol versi o n 7), or re d uce d d ose of be vaciz u ma b 
descri be d i n “s pecial c o nsi derati o ns” i n Secti o n 9. 1. 6 of t he pr ot oc ol. Partici pa nt s will be 
c o nsi dere d off st u d y u p o n i nitiati o n of treat me nt of t he t u m or wit h a n ot h er m o dalit y or i nitiati o n of 
h os pice care. T he st u d y will be c o nsi dere d c o m plete o nce e nr oll me nt has bee n met, f oll o w -u p 
pr oce d ures ha ve bee n c o n d ucte d o n all partici pa nt s, a n d data a nal ysis is c o ncl u de d. 
 


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
 
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L   
  
  
  
  
  
Pa ge 6    
  
  
  
  
2 7 J ul y 2 0 2 2  
 
1. 2.   
S C H E D U L E O F E V E N T S  
Ta ble 1  Sc he d ul e of St u d y Tests a n d Pr oce d ures f or I nitial lera p olt ure v Treat me nt  
Descri pti o n   
Scree ni n g:  
Wit hi n 6  
Wee ks  
Scree ni n g:  
Wit hi n 1 4  
D a ys Pri o r  
t o C at heter 
Pl ace me nt,  
b ut as Cl ose 
t o Bi o ps y as 
P ossi ble  
Scree ni n g:  
Wit hi n 2  
D a ys  
Pri or t o 
ler a p olt ure v 
 
C at heter  
Pl ace me nt  
Bi o ps y,  
ler a p olt ure v 
i nf usi o n 
P ost -I nf usi o n ( F oll o w-u p Peri o d) a 
O n -St u d y  
P artici p a nt s 
(re q uire d 
S O C  
Visits a n d 
Mi ni m u m  
F oll o w -u p)  
Off -St u d y  
P artici p a nt s 
( S O C Visits 
Wit h F oll o w -
u p)  
Wee k  
 
 
 
 
0   
1   
2   
4   
8   
[ W E E K 1 2 
VI SI T 
R E M O V E D 
I N 
P R O T O C O L 
V 7]  
1 2 b  
 
1 6 + 
E ver y 
9 
Wee ks 
U ntil 
Wee k 
5 2  
> 5 2  
(I nf or m ati o n 
Tr a ns mitte d  
R o uti nel y as  
O bt ai ne d)  
Fr o m Ti me Off  
St u d y 
A v ail a ble  
F or F oll o w -u p  
(I nf or m ati o n 
Tr a ns mitte d a  
Mi ni m u m of  
E ver y 6 
M o nt hs  
[ ± 1 M o nt h]) 
D a y  
 
Wit hi n  
1 4 D a ys  
Pri or t o  
C at heter  
Pl ace me nt  
Wit hi n  
2 D a ys  
Pri or t o  
ler a p olt ure v 
0  
1   
7   
1 4   
2 8   
5 6   
8 4  
1 1 2   
> 1 1 2   
V aries  
Ge ner al E v al u ati o ns  
I nf or me d 
C o nse nt  
X  
 
 
  
  
  
  
  
  
 
 
 
 
Cli nical 
assess me nt 
i ncl u di n g 
me dical hist or y)  
 
X  
 
  
X c 
X   
X   
X   
X   
X   
X   
X  
X  
P h ysical 
e xa mi nati o n 
 
X  
 
  
X c  
X   
X   
X   
X   
X   
X   
X  
 
Ne ur ol o gical 
e xa mi nati o n 
 
X  
 
  
X c  
X   
X   
X   
X   
X   
X   
X  
 


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
 
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L   
  
  
  
  
  
Pa ge 7    
  
  
  
  
2 7 J ul y 2 0 2 2  
 
Descri pti o n   
Scree ni n g:  
Wit hi n 6  
Wee ks  
Scree ni n g:  
Wit hi n 1 4  
D a ys Pri o r  
t o C at heter 
Pl ace me nt,  
b ut as Cl ose 
t o Bi o ps y as 
P ossi ble  
Scree ni n g:  
Wit hi n 2  
D a ys  
Pri or t o 
ler a p olt ure v 
 
C at heter  
Pl ace me nt  
Bi o ps y,  
ler a p olt ure v 
i nf usi o n 
P ost -I nf usi o n ( F oll o w-u p Peri o d) a 
O n -St u d y  
P artici p a nt s 
(re q uire d 
S O C  
Visits a n d 
Mi ni m u m  
F oll o w -u p)  
Off -St u d y  
P artici p a nt s 
( S O C Visits 
Wit h F oll o w -
u p)  
Wee k  
 
 
 
 
0   
1   
2   
4   
8   
[ W E E K 1 2 
VI SI T 
R E M O V E D 
I N 
P R O T O C O L 
V 7]  
1 2 b  
 
1 6 + 
E ver y 
9 
Wee ks 
U ntil 
Wee k 
5 2  
> 5 2  
(I nf or m ati o n 
Tr a ns mitte d  
R o uti nel y as  
O bt ai ne d)  
Fr o m Ti me Off  
St u d y 
A v ail a ble  
F or F oll o w -u p  
(I nf or m ati o n 
Tr a ns mitte d a  
Mi ni m u m of  
E ver y 6 
M o nt hs  
[ ± 1 M o nt h]) 
D a y  
 
Wit hi n  
1 4 D a ys  
Pri or t o  
C at heter  
Pl ace me nt  
Wit hi n  
2 D a ys  
Pri or t o  
ler a p olt ure v 
0  
1   
7   
1 4   
2 8   
5 6   
8 4  
1 1 2   
> 1 1 2   
V aries  
K P S  
 
X  
 
  
X c  
X   
X   
X   
X   
X   
X   
X  
 
A d verse e ve nts   
 
 
 
C o nti n u o us  
 
L a b or at or y E v al u ati o ns  
P V 
i m m u nizati o n 
b o oster d  
X  
 
 
  
  
  
  
  
  
 
 
 
 
C B C wit h 
differe ntial  
 
X  
 
  
X   
X   
X   
X   
X   
X   
X  
 
 
C M P  
 
X  
 
  
X   
X   
X   
X   
X   
X   
X  
 
 
P T, a P T T 
 
X  
 
  
  
  
  
  
  
 
 
 
 
Ser u m 
pre g na nc y test  
 
X  
X  
  
  
  
  
  
X e 
 
 
 
 
Ser u m f or L S Q, 
a nti -teta n us 
t o x oi d Ig G  
X ( pre -
b o ost)  
 
 
  
  
  
  
  
  
 
 
 
 


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
 
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L   
  
  
  
  
  
Pa ge 8    
  
  
  
  
2 7 J ul y 2 0 2 2  
 
Descri pti o n   
Scree ni n g:  
Wit hi n 6  
Wee ks  
Scree ni n g:  
Wit hi n 1 4  
D a ys Pri o r  
t o C at heter 
Pl ace me nt,  
b ut as Cl ose 
t o Bi o ps y as 
P ossi ble  
Scree ni n g:  
Wit hi n 2  
D a ys  
Pri or t o 
ler a p olt ure v 
 
C at heter  
Pl ace me nt  
Bi o ps y,  
ler a p olt ure v 
i nf usi o n 
P ost -I nf usi o n ( F oll o w-u p Peri o d) a 
O n -St u d y  
P artici p a nt s 
(re q uire d 
S O C  
Visits a n d 
Mi ni m u m  
F oll o w -u p)  
Off -St u d y  
P artici p a nt s 
( S O C Visits 
Wit h F oll o w -
u p)  
Wee k  
 
 
 
 
0   
1   
2   
4   
8   
[ W E E K 1 2 
VI SI T 
R E M O V E D 
I N 
P R O T O C O L 
V 7]  
1 2 b  
 
1 6 + 
E ver y 
9 
Wee ks 
U ntil 
Wee k 
5 2  
> 5 2  
(I nf or m ati o n 
Tr a ns mitte d  
R o uti nel y as  
O bt ai ne d)  
Fr o m Ti me Off  
St u d y 
A v ail a ble  
F or F oll o w -u p  
(I nf or m ati o n 
Tr a ns mitte d a  
Mi ni m u m of  
E ver y 6 
M o nt hs  
[ ± 1 M o nt h]) 
D a y  
 
Wit hi n  
1 4 D a ys  
Pri or t o  
C at heter  
Pl ace me nt  
Wit hi n  
2 D a ys  
Pri or t o  
ler a p olt ure v 
0  
1   
7   
1 4   
2 8   
5 6   
8 4  
1 1 2   
> 1 1 2   
V aries  
P V titer f 
X ( pre -
b o ost)  
X  
 
  
X g  
X h  
X   
  
X   
 
 
 
 
W h ole bl o o d f or 
i m m u n ol o gic/ 
ot her a nal ysis g  
X  
 
 
  
  
  
  
  
  
 
 
 
 
W h ole bl o o d f or 
b uff y c oat 
is olati o n 
X n  
 
 
  
  
  
  
  
  
 
 
 
 
St o ol sa m ple n  
X n  
 
 
  
  
  
  
  
X n  
 
 
 
 
Dise ase e v al u ati o ns  
M RI
l 
 
X  
 
  
  
  
  
X   
X   
 
X   
X  
X  
C T sca n  
 
 
 
X j 
  
  
  
  
  
 
 
 
 
Bi o ps y k  
 
 
 
X   
  
  
  
  
  
 
 
 
 
T u m or sa m ples   
 
 
 
  
  
  
  
  
  
 
  
X l 
X l 
Tre at me nt  


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
 
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L   
  
  
  
  
  
Pa ge 9    
  
  
  
  
2 7 J ul y 2 0 2 2  
 
Descri pti o n   
Scree ni n g:  
Wit hi n 6  
Wee ks  
Scree ni n g:  
Wit hi n 1 4  
D a ys Pri o r  
t o C at heter 
Pl ace me nt,  
b ut as Cl ose 
t o Bi o ps y as 
P ossi ble  
Scree ni n g:  
Wit hi n 2  
D a ys  
Pri or t o 
ler a p olt ure v 
 
C at heter  
Pl ace me nt  
Bi o ps y,  
ler a p olt ure v 
i nf usi o n 
P ost -I nf usi o n ( F oll o w-u p Peri o d) a 
O n -St u d y  
P artici p a nt s 
(re q uire d 
S O C  
Visits a n d 
Mi ni m u m  
F oll o w -u p)  
Off -St u d y  
P artici p a nt s 
( S O C Visits 
Wit h F oll o w -
u p)  
Wee k  
 
 
 
 
0   
1   
2   
4   
8   
[ W E E K 1 2 
VI SI T 
R E M O V E D 
I N 
P R O T O C O L 
V 7]  
1 2 b  
 
1 6 + 
E ver y 
9 
Wee ks 
U ntil 
Wee k 
5 2  
> 5 2  
(I nf or m ati o n 
Tr a ns mitte d  
R o uti nel y as  
O bt ai ne d)  
Fr o m Ti me Off  
St u d y 
A v ail a ble  
F or F oll o w -u p  
(I nf or m ati o n 
Tr a ns mitte d a  
Mi ni m u m of  
E ver y 6 
M o nt hs  
[ ± 1 M o nt h]) 
D a y  
 
Wit hi n  
1 4 D a ys  
Pri or t o  
C at heter  
Pl ace me nt  
Wit hi n  
2 D a ys  
Pri or t o  
ler a p olt ure v 
0  
1   
7   
1 4   
2 8   
5 6   
8 4  
1 1 2   
> 1 1 2   
V aries  
lera p olt ure v 
 
 
  
X ( + 1 -da y 
wi n d o w)  
  
  
  
  
  
 
 
 
 
L o m usti ne  
 
 
 
  
  
  
  
  
X m  
 
 
 
 
a P T T = acti vate d partial t hr o m b o plasti n ti me; C B C = c o m plete bl o o d c o u nt; C M P = C o m pre he nsi ve Meta b olic Pa nel; C T = c o m p ute d t o m o gra p h y; I g G = i m m u n o gl o b uli n 
G; K P S = Kar n ofs k y Perf or ma nce Stat us; L S Q = l y m p h oc yte s u bset q ua ntitati o n; M RI = ma g netic res o na nce i ma gi n g; P T = pr ot hr o m bi n ti me; P V = p oli o vir us; lera p olt ure v 
= p oli o/r hi n o vir us rec o m bi na nt; S A M = St u d y A d mi nistrati o n Ma n ual; S O C = sta n dar d of care.  
a.  Tests a n d pr oce d ures occ urri n g o n Da y 7 ha ve a ± 3 -da y wi n d o w. Fr o m Da y 1 4 ( Wee k 2) o n war d, all tes ts a n d pr oce d ures ha ve a ± 7-da y wi n d o w.  
b.   T he wee k 1 2 cli nic visit ( ± 1 wee k) a n d w h ole bl o o d c ollecti o n f or i m m u n ol o gic/ ot h er a nal ysis was re m o ve d i n pr ot oc ol v 7, as it was ass ociate d wit h f oll o w-u p 
after l o m usti ne use. Partici p a nt s e nr olle d u n der pr ot oc ol versi o n 7 a n d after will n ot ha ve a pr ot o c ol ma n date d wee k 1 2 visit.  
c.  Dail y after i nf usi o n u ntil disc har ge d fr o m h os pital; a P E m ust b e d oc u me nte d wit hi n 2 4 h ( ± 4 h) of disc har ge.  
d.   P V b o oster m ust occ ur ≥ 1 wee k ( b ut ≤ 6 wee ks) pri or t o t h e i nitial lera p olt ure v i nf usi o n. 
e.  O nl y f or w o me n of c hil d b eari n g p ote ntial w h o are ra n d o mize d t o recei v e l o m usti ne pri or t o pr ot o c ol V 7.  
f.  
F or scree ni n g pri or t o i nitial lera p olt ure v i nf usi o n, P V titers are t o be dra w n after i nf or me d c o nse nt a n d pri or t o P V b o oster a d mi nistrati o n. N o a d diti o nal t u bes nee d 
t o be draw n f or t he P V titer. T his a nal ysis ca n be d o ne fr o m t he w h ole bl o o d dra w n f or i m m u n ol o gic a nal ysis.  


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
 
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L   
  
  
  
  
  
Pa ge 1 0   
  
  
  
  
2 7 J ul y 2 0 2 2  
 
g.   W h ole bl o o d f or i m m u n ol o gic a nal ysis ( 3 m L at Da y 1 O R Da y 2 p ost -lera p olt ure v i nf usi o n; t hereafter, ~ 9 6. 5 m L; t u be a n d sa m ple pr ocessi n g a n d s hi p pi n g details 
o utli ne d i n la b orat or y ma n ual p orti o n of t he S A M). F or partici pa nt s o nl y at D U M C, a n a d diti o nal 6 ml ( ~ 1 0 2. 5 m L t otal) will be dra w n at b ot h t he pre -P V b o ost a n d 
p ost -P V scree ni n g visits ( bef ore lera p olt ure v i nf usi o n) a n d a gai n at t h e Wee k 1 visit as part of a s u b -st u d y at D U M C t o e x pl ore i nfla m mati o n-ass ociate d 
bi o mar kers, i m m u ne cell p he n ot y pe a n d i n nate a n d a da pti ve i m m u ne c o m pete nce. After Wee k 8, o nl y dra w 7 6. 5 m L of w h ole bl o o d f or all partici pa nt s/all ce nters. 
h.   Bl o o d sa m ple ( 6 m L) c ollecte d o n Da y 7 ( Wee k 1) p ost -i nf usi o n o nl y f or partici pa nts e nr olle d at D U M C c o nse nte d t o s u b-st u d y f or i m m u ne mar ker a nal yses. 
i.  
All M RIs i n t h e st u d y i ncl u de i ntra ve n o us a d mi nistrati o n of ga d oli ni u m. After wee k 5 2, M RIs are t o be c o n d ucte d per t he i nsti t uti o n’s S O C a n d all i ma ges are t o be 
tra ns mitte d t o t h e s p o ns or or t heir desi g nee n o less t ha n e ver y 6 m o nt hs ( ± 1 m o nt h) after t he last i ma ges were tra ns mitte d. 
j.  
T here is a p ost -cat h eter place me nt C T sca n a n d a p ost -cat h eter re m o val C T sca n.  
k.   Bi o ps y res ults s h o ul d be tra ns mi tte d, or bl oc ks/sli des s h o ul d be s hi p pe d t o t h e s p o ns or or desi g nee per i nstr ucti o ns i n t he la b orat or y ma n ual p orti o n of t he S A M.  
l.  
If a n y a d diti o nal sa m ples bec o me a vaila ble or resecti o ns occ ur a n yti me d uri n g t he st u d y ( ma ke partici p a nt  off st u d y) or off -stu d y f oll o w -u p peri o d, materials als o 
s h o ul d be tra ns mitte d t o t h e s p o ns or or t heir desi g nee, as o utli ne d i n t h e S A M, if p ossi ble.  
m.  F or partici p a nt s ra n d o mize d t o t he l o m usti ne c o h ort pri or t o pr ot o c ol v 7 recei v e d 1 1 0 m g/ m 2 oral l o m usti ne f or o ne c ycle at 8 wee ks p ost -lera p olt ure v i nf usi o n. 
Partici p a nt s w h o were o n be vaciz u ma b ( were treate d wit h be vaciz u ma b i n t he ti me si nce lera p olt ure v i nf usi o n) recei ve d 9 0 m g/ m 2 oral l o m usti ne f or o ne c ycle 8 
wee ks p ost -lera p olt ure v i nf usi o n. T h e l o m usti n e ma y ha ve bee n take n t h e da y of or 1 da y after t he wee k 8 visit.  
n.   St o ol Sa m ple f or O M NI ge ne Kit ( O M NI ge ne ®• G U T ( O M R -2 0 0)). F or ne wl y e nr olle d partici pa nt s (i.e., t h ose w h o ha ve n ot recei ve d lera p olt ure v u n der a pre vi o us 
pr ot oc ol versi o n), a kit will be dis pe nse d at t he pre -P V b o ost scree ni n g visit,  a n d t h e y will pr o vi d e a baseli ne sa m ple pri or t o lera p olt ure v i nf usi o n a n d a gai n after 
t he wee k 8 visit. F or partici pa nt s w h o recei v e d lera p olt ure v u n der a pre vi o us versi o n  of t he pr ot o c ol, a baseli ne/ pre -lera p olt ure v sa m ple will n ot be o btai ne d b ut t he 
partici p a nt  will be gi ve n a kit t o pr o vi de a p ost -lera p olt ure v i nf usi o n st o ol sa m ple at t heir ne xt cli nic visit.


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
 
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L   
  
  
  
  
  
Pa ge 1 1   
  
  
  
  
2 7 J ul y 2 0 2 2  
 
Ta ble 2.  Sc he d ule of St u d y Tests a n d Pr oce d ures f or L era p olt ure v  Retreat me nt  
St u d y Pr oce d ure  
Scree ni n g 
Peri o d  
ler a p olt ure v 
I nf usi o n 
P ost -I nf usi o n ( F oll o w-u p Peri o d)  
≤ 1 4 d a ys   
D a y 0   
D a y 1  
1 w  
( +/- 3 d)  
2 w  
( +/- 1 w)  
4 w  
( +/-1 w)  
8 w  
( +/-1 w)  
Q 9 -1 2 w 
f or 5 2 w 
> 5 2 Wee ks 
fr o m 
Retre at me nt b  
I nf or me d C o nse nta 
X  
 
 
 
 
 
  
 
 
Cli nical assess me nt a n d me dical hist or y   
X  
  
X d  
X   
X   
X   
X   
X   
X  
P h ysical E xa m c 
X  
  
X d  
X   
X   
X   
X   
X   
X  
Ne ur ol o gic E xa m  
X  
  
X d  
X   
X   
X   
X   
X   
X  
K P S  
X  
  
X d  
X   
X   
X   
X   
X   
X  
Rec or d Ca ncer treat me nts a n d 
C o nc o mita nt me dicati o ns e 
C o nti n u o us fr o m si g ni n g of I C F o n war d  
A d verse E ve nts  
 
C o nti n u o us  
P V I m m u nizati o n B o oster a n d A nti -
teta n us I g Gf 
X  
 
 
 
 
 
  
 
 
C B C w/ diff  
X  
 
X   
X   
X   
X   
X   
X  
 
C M P  
X  
 
X   
X   
X   
X   
X   
X  
 
P T, a P T T  
X  
 
 
 
 
 
  
 
 
Pre g na nc y Test g  
X  
 
 
 
 
 
  
 
 
M RI  
X  
 
 
 
 
X   
X   
X   
X  
C T Sca n  
 
X h  
 
 
 
 
  
 
 
Bi o ps y  
 
X  
 
 
 
 
  
 
 
lera p olt ure v 
 
X  
 
 
 
 
  
 
 
A Es = a d verse e ve nts; a P T T = acti vate d partial t hr o m b o plasti n ti me; C B C = c o m plete bl o o d c o u nt; C M P = c o m pre he nsi ve meta b olic  pa nel; C T = c o m p ute d t o m o gra p h y; I g G 
= i m m u n o gl o b uli n G; K P S = Kar n ofs k y Perf or ma nce Stat us; L S Q = l y m p h oc yte s u bset q ua ntitati o n; M RI = ma g netic res o na nce i ma gi n g; P T = pr ot hr o m bi n ti me; P V = 
p oli o vir us; S A E = seri o us a d verse e ve nts  
a.  I nf or me d C o nse nt m ust b e re ne we d pri or t o i nitiati o n of scree ni n g acti vities f or lera p olt ure v retreat me nt. 
b.   F oll o w -u p be y o n d Wee k 5 2 p ost retreat me nt: partici p a nts s h o ul d be f oll o we d per i nstit uti o nal S O C f or all assess me nts after Wee k 5 2 p ost lera p olt ure v retreat me nt. 
Data tra nsfers s h o ul d  occ ur n o > e ver y 3 m o nt hs (i ncl u di n g descri pti o n of M RI/t u m or meas ure me nts). If S O C occ urs less fre q ue ntl y, data s h o ul d be e n tere d wit hi n 
2 wee ks ( ± 1 wee k) of ac q uisiti o n.  
c.  P h ysical E xa mi n ati o n: T he scree ni n g p h ysical e xa mi n ati o n s h o ul d be a c o m plete p h ysical e xa m of maj or b o d y s yste ms, per i nstit uti o nal g ui deli nes. F oll o wi n g 
lera p olt ure v i nf usi o n, p h ysical e xa ms s h o ul d be f oc use d a n d s y m pt o m-directe d. Eac h e xa m s h o ul d be per f or me d i n c o nj u ncti o n wit h a ne ur ol o gical e xa m a n d K P S 
assess me nt.  
d.   P ost -lera p olt ure v (re)treat me nt: Cli nical assess me nt a n d p h ysical e xa mi n ati o ns (i ncl u di n g ne ur ol o gic assess me nt a n d K P S) s h o ul d be perf or me d da il y u ntil h os pital 
disc har ge.  


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
 
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L   
  
  
  
  
  
Pa ge 1 2   
  
  
  
  
2 7 J ul y 2 0 2 2  
 
e.  Ca ncer Treat me nt s a n d C o nc o mita nt Me dicati o ns: all start/st o p dates, d ose, r o ute, fre q ue nc y, pr oce d ures a n d treat me nts f or gli o ma or a n y ot he r ca ncer treat me nt are 
t o be rec or de d fr o m baseli ne o n war d, i n cl u di n g a ge nts ass ociate d wit h ma na gi n g lera p olt ure v a nti-t u m or i nflam mat or y res p o nse ( i.e., c ortic oster oi ds a n d 
be vaciz u ma b) or f or a n y ot h er a ge nts/ca uses.  
f.  
P oli o i m m u nizati o n b o oster a n d a nti -teta n us t o x oi d I g G bl o o d test: Ma y be o btai ne d l ocall y a n d m ust occ ur ≥ 1 wee k ( b ut ≤ 6 m o nt hs) pri or t o pla n ne d a d diti o nal 
lera p olt ure v i nf usi o n(s). 
g.   Pre g na nc y Test: A ser u m -base d pre g na nc y test m ust b e perf or me d f or all fe male partici p a nts d uri n g scree ni n g ( ≤ 2 da ys of lera p olt ure v i nf usi o n). 
h.   C T Sca n: I ncl u des a C T t o c o nfir m cat h eter place me nt pri or t o lera p olt ure v i nf usi o n ( prefera bl y i ntra o perati ve) a n d sec o n d C T u p o n cat heter re m o val t o c o nfir m n o 
blee d.  
 


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 3  
2 7 J ul y 2 0 2 2  
 
1. 3.   
G L O S S A R Y O F A B B R E VI A TI O N S  
A b bre vi ati o n  
Defi niti o n  
A E  
A d verse E ve nt  
A E SI  
A d verse E ve nt of S pecial I nterest  
A L T  
Ala ni ne A mi n otra nsferase  
A S T  
As partate A mi n otra nsferase  
A T C  
A nat o mical T hera pe utic Classificati o n  
B MI  
B o d y Mass I n de x  
B S A  
B o d y S urface Area  
C E D  
C o n vecti o n E n ha nce d Deli ver y  
CI  
C o nfi de nce I nter val  
C N S  
Ce ntral Ner v o us S yste m  
C R  
C o m plete Res p o nse  
C R F  
Case Re p ort F or m  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
D C R  
Disease C o ntr ol Rate  
D O R  
D urati o n of Res p o nse  
D U M C  
D u ke U ni versit y Me dical Ce nter  
E D C  
Electr o nic Data Ca pt ure  
F A S  
F ull A nal ysis Set  
H M G B 1  
Hi g h M o bilit y Gr o u p 1 B o x  
I C E 
I nterc urre nt E ve nts 
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n  
i R A N O 
I m m u n ot hera p y Res p o nse Assess me nt i n Ne ur o-
O nc ol o g y  
I S C 
I n vesti gat or Steeri n g C o m mittee 
K P S  
Kar n ofs k y Perf or ma nce Stat us  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M R  
Mi n or Res p o nse  
M RI  
Ma g netic Res o na nce I ma gi n g  
n  
Partici pa nt s 
N E  
N ot E val ua ble  
N K  
Nat ural Killer  
O M R -2 0 0  
O M NI ge ne ®• G U T  
O R R  
O bjecti ve Res p o nse Rate  
O S  
O verall S ur vi val  
P D  
Pr o gressi ve Disease  


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 4  
2 7 J ul y 2 0 2 2  
 
P R  
Partial Res p o nse  
P T  
Preferre d Ter m  
P V  
P oli o vir us  
L era p olt ure v 
O nc ol ytic P oli o/ R hi n o vir us Rec o m bi na nt  
S A E  
Seri o us A d verse E ve nt  
S A F  
Safet y  
S D  
Sta ble Disease  
S D  
Sta n dar d De viati o n  
T E A E  
Treat me nt -E mer ge nt A d verse E ve nt  
T E S A E  
Treat me nt -E mer ge nt Seri o us A d verse E ve nts  
U L N  
U p per Li mit N or mal  
W H O  
W orl d Healt h Or ga nizati o n  
W H O -D D  
W H O Data Dicti o nar y  
 


Istari O nc ol o g y I nc. 
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Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 5  
2 7 J ul y 2 0 2 2  
 
2.   
O B J E C TI V E S  
O bjecti ve  
E n d p oi nt  
Pri m ar y  
•  
Assess t he a nti -t u m or res p o nse a n d d urati o n of 
res p o nse a m o n g a d ults wit h rec urre nt W H O 
gra de I V mali g na nt gli o ma treate d wit h 
lera p olt ure v 
•  
O bjecti ve res p o nse rate ( O R R)  
•  
D urati o n of res p o nse ( D O R)  
Sec o n d ar y  
•  
Assess s ur vi val o utc o mes of a d ults wit h 
rec urre nt W H O gra de I V mali g na nt gli o ma 
treate d wit h lera p olt ure v relati ve t o a criteria 
matc he d e xter nal ( hist orical) c o ntr ol gr o u p  
•  
La n d mar k S ur vi val  
•  
O verall s ur vi val ( O S)  
•  
Assess t he safet y of lera p olt ure v 
•  
T he pr o p orti o n of partici pa nt s wit h 
gra de 3, 4, or 5 treat me nt -relate d 
a d verse e ve nts 
•  
Assess t he disease c o ntr ol rate f oll o wi n g 
lera p olt ure v i nf usi o n 
•  
Disease C o ntr ol Rate ( D C R)  
E x pl or at or y  
•  
Descri be c ha n ges vis ualize d o n i ma gi n g d ue t o 
i ntrat u m oral i n oc ulati o n of lera p olt ure v 
•  
Descri pti o n of i ma gi n g c ha n ges  
•  
Assess i m m u n ol o gic res p o nses i n peri p heral 
bl o o d a n d i n ser u m  
•  
C ha n ge fr o m baseli ne i n i m m u ne 
f u ncti o n 
•  
I de ntif y ge netic pre dict ors of res p o nse or fail ure 
of res p o nse (i ncl u di n g i n b uff y c oat) t o 
treat me nt wit h lera p olt ure v 
•  
I de ntificati o n of ge netic mar kers as 
pre dict ors of res p o nse  
•  
T o o btai n t he q ua ntitati ve g ut micr o bi o me 
pr ofile via t he O M NI ge ne ®• G U T ( O M R -2 0 0) 
kit t o deter mi ne a n y p ote ntial i nfl ue nce i n 
res p o nse t o lera p olt ure v 
•  
I de ntificati o n of q ua ntitati ve g ut 
micr o bi o me pr ofile as pre dict ors of 
res p o nse 
•  
As part of a s maller s u b -st u d y o nl y at D u ke 
U ni versit y Me dical Ce nter  (D U M C ), t o e x pl ore 
i nfla m mati o n-ass ociate d bi o mar kers, i m m u ne 
cell p he n ot y pe a n d i n nate a n d a da pti ve i m m u ne 
c o m pete nce pre - a n d p ost -p oli o vir us ( P V ) b o ost 
( pri or t o i nf usi o n) a n d p ost-lera p olt ure v 
i nf usi o n 
•  
I nfla m mati o n-ass ociate d bi o mar kers, 
i m m u ne cell p he n ot y pe a n d i n nate 
a n d a da pti ve i m m u ne c o m pete nce  
•  
Assess a nti -t u m or res p o nses a n d o utc o mes 
f oll o wi n g lera p olt ure v retreat me nt(s) or 
treat me nt wit h a n y ot her n o n-pr ot oc ol s pecifie d 
t hera p y 
•  
Descri pti o n of t he pr o p orti o n of 
partici pa nt s w h o ac hie ve c o m plete 
res p o nse ( C R), partial res p o nse ( P R), 
mi n or res p o nse ( M R), sta ble disease 
( S D) (al o n g wit h ass ociate d 
d urati o ns) f oll o wi n g lera p olt ure v 
retreat me nt 


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 6  
2 7 J ul y 2 0 2 2  
 
O bjecti ve  
E n d p oi nt  
•  
Assess a nti -t u m or res p o nses a n d o utc o mes 
c o nsi deri n g site -le vel e x perie nce wit h 
lera p olt ure v treat me nt 
•  
Descri pti o n of partici p a nt o utc o mes 
f oll o wi n g lera p olt ure v i nf usi o n i n 
ce nters base d o n t he n u m ber of pri or 
partici pa nt s i nf use d 
 
3.   
G E N E R A L S T A TI S TI C A L C O N SI D E R A TI O N S  
3. 1.   
S A M P L E SI Z E  A N D P O W E R  
T he sa m ple size of t he st u d y is a p pr o xi matel y 1 2 2 partici pa nts. A f or mal sa m ple size calc ulati o n 
was n ot perf or me d. T he f oll o wi n g ta ble s h o ws t he O R R i n perce nt a n d t he c orres p o n di n g 9 5 % 
c o nfi de nce i nter vals  ( CI) as a f u ncti o n of t he n u m ber of o bjecti ve res p o nses, if f or e xa m ple 1 2 0 
partici pa nt s were e nr olle d. 
 
Ta ble 3  Sa m ple Size Calc ulati o n  
N u m ber of 
P artici p a nt s  
N u m ber of 
o bjecti ve 
res p o nses  
O R R ( %)   
9 5 % CI  
1 2 0  
1 0  
8. 3 %  
3. 4 %, 1 3. 3 %  
1 2 0  
1 2  
1 0. 0 %   
4. 6 %, 1 5. 4 %  
1 2 0  
1 4  
1 1. 7 %   
5. 9 %, 1 7. 4 %  
1 2 0  
1 6  
1 3. 3 %   
7. 3 %, 1 9. 4 %  
1 2 0  
1 8  
1 5. 0 %   
8. 6 %, 2 1. 4 %  
1 2 0  
2 0  
1 6. 7 %   
1 0. 0 %, 2 3. 3 %  
 
3. 2.   
H A N D LI N G O F D A T A  
3. 2. 1.   
Str at a a n d C o v ari ates  
Partici pa nt  ra n d o mizati o n u n til pr ot oc ol  a me n d me nt 7 was stratifie d b y ce nter.  
 
3. 2. 2.   
M ulti ple Testi n g a n d C o m p aris o ns   
All a nal yses will be c o n d ucte d wit h o ut a dj ust me nts f or m ulti ple c o m paris o ns.  
 
3. 2. 3.   
Missi n g D at a  a n d O utliers  
E ver y eff ort will be ma de t o o btai n re q uire d data at eac h sc he d ule d e val uati o n fr o m all partici pa nt s 
w h o ha ve bee n ra n d o mize d. I n sit uati o ns w here it is n ot p ossi ble t o o btai n all data, it ma y be 
necessar y t o i m p ute  missi n g data. T hese sit uati o ns are descri be d bel o w. U nless ot her wise s pecifie d, 
all ot her missi n g data will  n ot be i m p ute d.  
 


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 7  
2 7 J ul y 2 0 2 2  
 
3. 2. 3. 1.   
Missi n g Se verit y or Rel ati o ns hi p f or A d verse E ve nts  
A d verse e ve nts  ( A E) wit h missi n g se verit y will ha ve t he se verit y i m p ute d as “ Gra de 3” f or t he A E 
ta b ulati o ns. A d verse e ve nts wit h missi n g relati o ns hi p t o st u d y dr u g will ha ve t he relati o ns hi p 
i m p ute d as ‘ Defi nite’ f or t he A E ta b ulati o ns if t he A E starte d o n or after cat heter place me nt. 
 
3. 2. 3. 2.   
I m p ut ati o n of I nc o m plete D ates 
A n i nc o m plete date occ urs w he n t he e xact date a n e ve nt occ urre d or e n de d ca n n ot be o btai ne d fr o m 
a partici pa nt . T he data base c o ntai ns data fiel ds f or m o nt h, da y, a n d year. A date is i nc o m plete if at 
least o ne of t hese t hree fiel ds is n ot k n o w n. F or ma n y of t he pla n ne d a nal yses, a c o m plete date is 
necessar y t o deter mi ne if t he e ve nt s h o ul d be i ncl u de d i n t he a nal ysis (i.e., if t he e ve nt is treat me nt -
e mer ge nt) or t o esta blis h t he d urati o n of a n e ve nt. I n s uc h cases, i nc o m plete dates will be i m p ute d . 
 
F or t he p ur p oses of ha n dli n g partiall y re p orte d start a n d st o p dates f or a n e ve nt , e xcl u di n g 
de xa met has o ne use,  t he f oll o wi n g al g orit h m will be a p plie d:  
1)  F or o nset date:  
a) If o nl y t he da y part of t he o nset date is missi n g a n d occ urs i n t he sa me m o nt h a n d year as 
t he date of d ose of st u d y dr u g, t he date of d ose of st u d y dr u g will be use d as t he o nset date. 
Ot her wise, t he first da y of t he m o nt h will be use d t o c o m plete t he o nset date . 
b)  If t he da y a n d m o nt h parts of t he o nset date are missi n g a n d occ ur i n t he sa me year as t he 
d ose of st u d y dr u g, t he date of t he d ose of st u d y dr u g will be use d as t he o nset date. 
Ot her wise, Ja n uar y 1st will be use d t o c o m plete t he o nset date.  
c) If t he o nset date is c o m pletel y missi n g, t he date of t he d ose of st u d y dr u g will be use d as 
t he o nset date. 
2)  F or e n d date:  
a) If o nl y t he da y part of t he e n d date is missi n g, t he last da y of t he m o nt h will be use d t o 
c o m plete t he e n d date.  
b)  If t he da y a n d m o nt h parts of t he e n d date are missi n g, Dece m ber 3 1st will be use d t o 
c o m plete t he e n d d ate. 
c) If t he e n d date is c o m pletel y missi n g, t he ma xi m u m of t he partici pa nt’s off st u d y date or 
date of last c o ntact  will be use d as t he e n d date.  
 
F or t he p ur p ose s of ha n dli n g partiall y re p orte d e n d dates f or de xa met has o ne use, t he f oll o wi n g 
al g orit h m will be a p plie d: 
1)  If a partici pa nt has m ulti ple e ntries of de xa met has o ne use a n d o ne of t he m has a start date pri or 
t o a s u bse q ue nt e ntr y a n d t here is n o e n d date t o t he first e ntr y, t he da y bef ore t he start date of 
t he s u bse q ue nt rec or d will be use d as t he e n d date . 
2)  If a partici pa nt has m ulti ple e ntries of de xa met has o ne use a n d o ne of t he m has n o e n d date a n d 
n o s u bse q ue nt rec or ds , t he ma xi m u m of eit her  t he partici pa nt’s off st u d y date or t he date of last 
c o ntact will be use d as t he e n d date.  
 
If a n y i m p ute d start date ca uses t he start date t o occ ur after t he e n d date, t he e n d date will be use d 
f or t he i m p utati o n of t he start date. If a n y i m p ute d e n d date ca uses t he e n d date t o occ ur pri or t o t he 
start date of t he e ve nt, t he start date of t he e ve nt will be use d f or t he i m p utati o n of t he e n d date. 
 


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 8  
2 7 J ul y 2 0 2 2  
 
3. 2. 4.   
Prese nt ati o ns b y St u d y Visit  
W he n data are c ollecte d seriall y o ver ti me, i n di vi d ual data prese ntati o ns ma y i ncl u de b y -st u d y visit 
dis pla ys. B y -st u d y visit dis pla ys will o nl y be s u m marize d u p t o Wee k 5 2. Visits  will be prese nte d 
acc or di n g t o t he n o mi nal visit as o btai ne d fr o m t he C R F . If m ulti ple o bser vati o ns are c ollecte d at a 
sc he d ule d visit, t he cl oset o bser vati o n t o t he tar get da y will be c h ose n. If t w o o bser vati o ns ha ve 
e q ual dista nce fr o m t he tar get da y b ut o ne is earlier a n d t he ot her is later t ha n t he tar get da y, t he 
earlier o bser vati o n will be c h ose n.  U nsc he d ule d assess me nts will be i ncl u de d i n t he listi n gs.  
 
3. 2. 5.   
Prese nt ati o ns b y W orse C ase  
W he n data are c ollecte d seriall y o ver ti me, i n di vi d ual data prese ntati o ns ma y i ncl u de “ w orst case 
o n st u d y” dis pla ys.  I n t h ose sit uati o ns, b ot h sc he d ule d a n d u nsc he d ule d assess me nts u p t o 5 2 
wee ks will be i ncl u de d.  
 
3. 2. 6.   
Defi niti o ns a n d Ter mi n ol o g y   
A ge  
A ge is a ge at i nf or me d c o nse nt a n d is as ca pt ure d o n t he C R F.  
 
Baseli n e Val ue 
F or p ur p oses of a nal ysis, t he baseli ne val ue is defi ne d as t he last n o n -missi n g val ue o btai ne d pri or 
t o i nitiati o n of st u d y dr u g. Rec or ds wit h missi n g ti me o n t he date of i nitiati o n of st u d y dr u g will n ot 
be c o nsi dere d p ost -Baseli ne.  
 
Da y 1  ( Baseli ne) 
Da y 1  is t he earliest da y t hat st u d y dr u g is i nitiate d. N ote t hat t his is a c ha n ge fr o m t he pr ot oc ol 
w here t he first da y of st u d y dr u g a d mi nistrati o n was desi g nate d as Da y 0.  
 
St u d y Da y   
St u d y Da y is defi ne d relati ve t o Baseli ne  (Da y 1 ). T h us, t he st u d y da y of a n e ve nt is calc ulate d as: 
 
St u d y Da y = e ve nt date –  date of Da y 1  ( + 1, if e ve nt date ≥ date of Da y 1). 
 
St u d y Visit  
St u d y Visit is t he n o mi nal visit as rec or de d o n t he C R F.    
 
C ha n ge fr o m Baseli ne   
C ha n ge fr o m baseli ne f or a gi ve n e n d p oi nt is defi ne d as t he St u d y Da y X val ue mi n us t he Baseli ne 
V al ue. 
 
Da ys o n St u d y  
Da ys o n st u d y is t he n u m ber of da ys fr o m Da y 1  t o t he date of st u d y c o m pleti o n as rec or de d o n t he 
Off St u d y C R F pa ge.  
 
 


Istari O nc ol o g y I nc. 
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Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
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A d verse E ve nt  
A n A E is a n y u nt o war d me dical occ urre nce i n a partici pa nt  recei vi n g st u d y dr u g(s) a n d w hic h d oes 
n ot necessaril y ha ve a ca usal relati o ns hi p wit h t his treat me nt. F or t his pr ot oc ol, t he defi niti o n of 
A E als o i ncl u des w orse ni n g of a n y pree xisti n g me dical c o n d iti o n. A n A E ca n t heref ore be a n y 
u nfa v ora ble a n d u ni nte n de d or w orse ni n g si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), 
s y m pt o m, or disease te m p orall y ass ociate d wit h cat heter place me nt or t he use of lera p olt ure v, 
l o m usti ne (f or partici pa nt s ra n d o mize d t o t his ar m pri or t o pr ot oc ol versi o n 7), be vaciz u ma b, or 
c ortic oster oi ds w het her or n ot relate d t o use of a n y of t hese dr u gs. All a d verse e ve nts will be 
rec or de d o n t he A d verse E ve nt C R F. 
 
Treat me nt -e mer ge nt  A d verse E ve nt  ( T E A E) 
A T E A E will be a n A E t hat occ urre d d uri n g t he st u d y o n or after cat heter place me nt . A d diti o nall y, 
it is ass u me d t hat a n A d verse Eve nt w hic h was r e p orte d t o ha ve starte d o n Da y 1  wit h o ut a n 
ass ociate d o nset ti me occ urre d o n or after cat heter place me nt . 
 
A d verse E ve nt of S pecial I nterest  ( A E SI) 
A n A E SI is a n y gra de 3 or gra de 4 t o xicit y c o nsi dere d relate d ( p ossi bl y, pr o ba bl y,  or defi nitel y) t o 
a pr ot oc ol treat me nt (i ncl u des s ur gical bi o ps y/i nf usi o n pr oce d ure, lera p olt ure v, l o m usti ne (f or 
partici pa nt s ra n d omize d t o t his ar m pri or t o pr ot oc ol versi o n 7), be vaciz u ma b, c ortic oster oi ds) t hat 
is n ot re versi ble (i.e., d oes n ot i m pr o ve t o ≤ gra de 2 wit h e xce pti o n of ne ur ol o gic e ve nts, w hic h 
m ust o nl y i m pr o ve fr o m hi g hest gra de le vel t o ne xt l o wer gra de le vel) wit hi n 2 wee ks. T his 
i ncl u des a n y treat me nt-relate d life-t hreate ni n g e ve nt or a n y treat me nt-relate d deat h. A n y gra de 2 or 
hi g her seri o us a ut oi m m u ne t o xicities — partic ularl y t h ose affecti n g vital or ga ns ( e. g., car diac, re nal, 
ce ntral ner v o us s yste m ( C N S ))— will al s o be c o nsi dere d a n A E SI if t he y occ ur wit hi n 2 wee ks of 
a n y pr ot oc ol treat me nt, w het her t he A E re q uires i nter ve nti o n.  
 
E xce pti o ns t o A E SIs are liste d i n pr ot oc ol Secti o n 1 2. 8. 6. A E SIs will be c ollecte d o n t he A d verse 
E ve nt C R F.  
 
C o nc o mita nt Me dicati o ns  
C o nc o mita nt me dicati o ns are t h ose me d icati o ns ta ke n o n or after cat heter place me nt .  T his 
defi niti o n i ncl u des me dicati o ns sta rte d pri or t o cat heter place me nt  b ut  c o nti n ui n g c o nc o mita ntl y 
wit h st u d y dr u g. 
 
Pri or Me dicati o ns  
Pri or me dicati o ns are t h ose me dicati o ns ta ke n a n d disc o nti n ue d pri or t o cat heter place me nt . 
 
I m m u n ot hera p y Res p o nse Assess me nt i n Ne ur o-O nc ol o g y (i R A N O)  
i R A N O are g ui deli nes t hat i nc or p orate criteria pre vi o usl y defi ne d b y t he R A N O w or ki n g 
c o m mittee t o define C R, P R, M R , S D, pr o gressi ve disease ( P D ), a n d n o n-e val ua ble, f or 
partici pa nt s wit h mali g na nt gli o ma, l o w-gra de gli o ma, a n d brai n metastases. T he ke y c o m p o ne nt of 
i R A N O is s pecific a d diti o nal g ui da nce f or t he deter mi nati o n of P D a m o n g ne ur o-o nc ol o g y 
part ici pa nts u n der g oi n g i m m u n ot hera p y. i R A N O g ui deli nes re q uire co nfir mati o n of pr o gressi o n o n 
f oll o w-u p i ma gi n g 3 m o nt hs after i nitial ra di o gra p hic pr o gressi o n i f: 


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 0  
2 7 J ul y 2 0 2 2  
 
1.  N o ne w or si g nifica ntl y w orse ne d ne ur ol o gic deficits n ot d ue t o c o -m or bi d e ve nt or c o nc urre nt 
me dicati o n A N D  
2.  ≤ 6 m o nt hs fr o m i nitiati o n of i m m u n ot hera p y  
If f oll o w-u p i ma gi n g c o nfir ms pr o gressi o n, t he date of act ual pr o gressi o n s h o ul d be bac k date d  t o 
t he date of i nitial ra di o gra p hic pr o gressi o n. A p peara nce of ne w lesi o ns s olel y d oes n o t defi ne 
pr o gressi ve disease  ≤ 6 m o nt hs fr o m i nitiati o n of i m m u n ot hera p y. T he lesi o ns are a d de d t o t he 
t otal lesi o n areas f or f oll o w-u p assess me nts.  
 
C o m plete Res p o nse  ( C R) 
C R is defi ne d as:  
• 
Disa p peara nce  of all e n ha nci n g disease f or ≥ 4 wee ks A N D  
• 
N o ne w l esi o ns A N D 
• 
Sta ble/i m pr o ve d T 2/ F L AI R A N D  
• 
N o m ore t ha n p h ysi ol o gic ster oi ds A N D  
• 
Sta ble  i m pr o ve d cli nicall y 
 
Partial Res p o nse ( P R)  
P R is defi ne d b y:  
• 
≥ 5 0 % decrease i n t he s u m of bi per pe n dic ular dia meters of e n ha nci n g disease f or ≥ 4 wee ks 
A N D  
• 
N o ne w lesi o ns A N D  
• 
Sta ble/i m pr o ve d T 2/ F L AI R A N D  
• 
Sta ble/i m pr o ve d ster oi ds A N D  
• 
Sta ble/i m pr o ve d cli nicall y  
 
Sta ble Disease ( S D)  
S D is defi ne d b y:  
• 
D oes n ot q ualif y f or C R, P R, P D A N D  
• 
N o ne w lesi o ns A N D  
• 
Sta ble/i m pr o ve d T 2/ F L AI R A N D  
• 
Sta ble/i m pr o ve d ster oi ds A N D  
• 
Sta ble/i m pr o ve d cli nicall y  
 
Pr o gressi ve Disease ( P D)  
P D is defi ne d b y:  
• 
≥ 2 5 % i ncrease i n t he s u m of bi per pe n dic ular dia meters of e n ha nci n g disease O R 
• 
Ne w lesi o ns O R  


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 1  
2 7 J ul y 2 0 2 2  
 
• 
Si g nifica nt w orse ne d T 2/ F L AI R O R  
• 
Si g nifica nt cli nical decli ne  
 
I m m u n o pr o gressi o n/I m m u n ores p o nse 
I n a d diti o n t o t he cate g ories of res p o nse defi ne d i n i R A N O, t he pr ot oc ol ha d t w o a d diti o nal 
cate g ories of res p o nse: i m m u n o pr o gressi o n a n d i m m u n ores p o nse t hat c o ul d be c h ose n as t he ti me 
p oi nt res p o nse or best o verall res p o n se. Per t he C R F c o m pleti o n g ui deli nes, i m m u n o pr o gressi o n 
a n d i m m u n ores p o nse s h o ul d be c h ose n i n t he f oll o wi n g setti n gs:  
• 
I m m u n o pr o gressi o n: Mar ke d i ncrease i n c o ntrast e n ha nce me nt p ossi bl y d ue t o i m m u n ot hera p y 
(t his deter mi nati o n is o utsi de t he rec o m me n de d assess me nt deter mi nati o ns of R A N O a n d is 
P V S RI P O s pecific). I m m u n o pr o gressi o n will be selecte d w he n t here is si g nifica nt pr o ba bilit y 
of, or c o ncer n f or, i m m u n o pr o gressi o n o ver tr ue disease pr o gressi o n.  
• 
I m m u n ores p o nse: Mar ke d decrease i n c o ntrast e n ha nce me nt p ossi bl y d ue t o i m m u n ot hera p y 
(t his deter mi nati o n is o utsi de t he rec o m me n de d assess me nt deter mi nati o ns of R A N O a n d is 
P V S RI P O s pecific).  
 
O bjecti ve Res p o nse Rate ( O R R)  
O R R is defi ne d as t he pr o p orti o n of partici pa nt s ac hie vi n g c o m plete res p o nse C R or P R base d o n 
i R A N O criteria. 
 
D urati o n of Res p o nse ( D O R)  
D O R is defi ne d as ti me fr o m C R or P R u ntil c o nfir me d P D  or deat h, ce ns ori n g at t he date of t he 
last i ma gi n g wit h o ut c o nfir me d P D pri or t o t he date t he s u bject is c o nsi dere d off-st u d y. 
 
La n d mar k  S ur vi val  
La n d mar k s ur vi val is defi ne d as t he pr o p orti o n of partici pa nt s ali ve starti n g ≥ m o nt h 3 6 after 1 st 
lera p olt ure v i nf usi o n. 
 
O verall S ur vi val ( O S)  
O S is defi ne d as ti me fr o m lera p olt ure v i nf usi o n t o deat h fr o m a n y ca use, or last f oll o w-u p if 
partic i pa nt is ali ve. 
 
Disease C o ntr ol Rate ( D C R)  
D C R is defi ne d as t he pr o p orti o n of partici pa nt s ac hie vi n g C R, P R, or S D . 
 
Treat me nt Peri o d  
Treat me nt peri o d is defi ne d as t he peri o d fr o m cat heter place me nt t o Wee k 5 2.  
 
3. 3.   
TI MI N G O F A N A L Y S E S  
T he fi nal a nal ysis will be c o m plete d after t he last partici pa nt  c o m pletes or disc o nti n ues t he st u d y 
a n d t he res ulti n g cli nical data base has bee n clea ne d, q ualit y c hec ke d, a n d l oc ke d.  
 


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 2  
2 7 J ul y 2 0 2 2  
 
4.   
A N A L Y SI S P O P U L A TI O N S  
Data a nal yses will be base d o n t he  f ull a nal ysis ( FA S)  a n d safet y ( S A F) a nal ysis sets .  
 
4. 1.   
F U L L A N A L Y SI S S E T  
T he f ull a nal ysis set ( F A S) i ncl u des s u bjects t hat were ra n d o mize d , has a n i nf usi o n cat heter place d, 
a n d recei ve d t he i nitial d ose of lera p olt ure v . T his will be t he pri mar y p o p ulati o n use d f or t he 
efficac y a nal yses. Patie nts i n t his p o p ulati o n will be a nal yze d base d o n assi g ne d treat me nt.  T h ose 
partici pa nt s ra n d o mize d t o lera p olt ure v + l o m usti ne after pr ot oc ol versi o n 7  (1 0 6 8,  1 0 7 0,  1 0 7 3,  
1 0 7 4,  1 0 7 8,  1 0 8 2,  1 0 8 3,  4 0 0 5,  a n d 4 0 0 8 ) are c o nsi dere d assi g ne d t o t he lera p olt ure v o nl y ar m  
si nce t he y di d n ot act uall y recei ve l o m usti ne. 
 
4. 2.   
S A F E T Y S E T  
 
T he safet y ( S A F) set i ncl u des all e nr olle d partici pa nt s w h o ha d a n i nf usi o n cat heter place d . T his 
will be t he pri mar y p o p ulati o n use d f or t he safet y a nal yses. Partici pa nt s i n t his p o p ulati o n will be 
a nal yze d acc or di n g t o t he treat me nt w hic h t he y recei ve.  
 
 
5.   
S T A TI S TI C A L M E T H O D S  
Descri pti ve statistical met h o ds will be use d t o s u m marize t he data fr o m t his st u d y . U nless state d 
ot her wise, t he ter m “ descri pti ve statistics” refers t o n u m ber of partici pa nt s ( n), mea n, me dia n, 
sta n dar d de viati o n, mi ni m u m a n d ma xi m u m f or c o nti n u o us data a n d fre q ue ncies a n d per ce nta ges 
f or cate g orical data. 
 
S ur vi val esti mates will be a nal yze d wit h Ka pla n -Meier met h o d a n d s u m marize d wit h me dia n, 
t we nt y-fift h a n d se ve nt y-fift h perce ntiles, a n d 9 5 % c o nfi de nce i nter vals ( CI), if a p plica ble. All data 
c ollecte d d uri n g t he st u d y will be i ncl u de d i n data listi n gs. U n less ot her wise n ote d, t he data will be 
s orte d first b y treat me nt, partici pa nt , a n d t he n b y date wit hi n eac h partici pa nt  n u m ber.  
All s u m mar y ta bles  a n d fi g ures will be prese nte d b y treat me nt gr o u p a n d o verall. T he ter m 
“treat me nt gr o u p” refers t o treat me nt wit h lera p olt ure v or lera p olt ure v a n d l o m usti ne. 
 
A nal yses will be i m ple me nte d usi n g S A S ® 9. 4 or hi g her ( S A S I nstit ute, Car y, N ort h Car oli na, 
U S A). T he I nter nati o nal C o nfere nce o n Har m o nizati o n (I C H) n u m beri n g c o n ve nti o n, i.e., I C H-E 3, 
will be use d f or all ta bles a n d listi n gs. U p o n c o m pleti o n, all S A S ®  pr o gra ms will be vali date d b y 
a n i n de pe n de nt pr o gra m mer wit hi n t he staff of t he t hir d -part y ve n d or d oi n g  t he pri mar y a nal ysis. 
T he vali dati o n pr ocess will be use d t o c o nfir m t hat statisticall y vali d met h o ds ha ve bee n 
i m ple me nte d a n d t hat all data tra nsf or mati o ns a n d calc ulati o ns are acc urate. C hec ks will be ma de 
t o e ns ure acc urac y, c o nsiste nc y wit h t his pla n, c o nsiste nc y wit hi n ta bles, a n d c o nsiste nc y bet wee n 
ta bles a n d c orres p o n di n g data listi n gs. All d oc u me nts will be verifie d b y t he lea d statisticia n t o 
e ns ure acc urac y a n d c o nsiste nc y of a nal yses.  
 


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 3  
2 7 J ul y 2 0 2 2  
 
5. 1.   
P A R TI CI P A N T  DI S P O SI TI O N, D E M O G R A P HI C A N D B A S E LI N E 
C H A R A C T E RI S TI C S  
Partici pa nt  dis p ositi o n will be prese nte d f or all  e nr olle d  partici pa nt s, w here e nr olle d is defi ne d as 
partici pa nts t hat si g ne d i nf or me d c o nse nt . S u m maries will be prese nte d base d o n treat me nt 
recei ve d. A s u m mar y ta ble will be ge nerate d b y treat me nt gr o u p a n d o verall. T he n u m ber of 
partici pa nt s w h o were scree ne d, scree n fail ures, a n d t he reas o n f or scree n fail ure will be 
s u m marize d. A d diti o nall y, t he n u m ber of partici pa nt s i n eac h a nal ysis p o p ulati o n will be 
s u m marize d. T he  e n d of st u d y stat us a n d reas o n t he partici pa nt  was ta ke n off st u d y  will be 
pr o vi de d. Si milarl y, t he pri mar y reas o n f or deat h will be prese nte d. A d diti o nall y, t he n u m ber of 
da ys o n st u d y will be  s u m marize d. Partici pa nt  dis p ositi o n i ncl u di n g treat me nt gr o u p, a nal ysis 
p o p ulati o n , e n d of st u d y stat us a n d reas o n, a n d deat h date a n d  reas o n will be liste d. 
 
De m o gra p hic data a n d baseli ne c haracteristics i ncl u di n g a ge  at i nf or me d c o nse nt , ge n der, race, 
et h nicit y, Kar n ofs k y perf or ma nce stat us ( K P S) at Baseli ne  a n d Baseli ne  vital si g ns ( hei g ht, wei g ht , 
a n d b o d y s urface area ( B S A) ) will be s u m marize d usi n g descri pti ve statistics.  Fre q ue nc y of K P S 
sc ores < 7 0, 7 0, 8 0, 9 0, a n d 1 0 0 will be s u m marize d b y treat me nt gr o u p a n d o verall. De m o gra p hic 
data a n d baseli ne c haracteristics will be liste d.  
5. 2.   
DI S E A S E C H A R A C T E RI S TI C S  
Disease c haracteristics i ncl u di n g disease stat us, descri pti o n  ( U nif ocal or M ultif ocal) , s ur gical 
pat h ol o g y dia g n osis , hist ol o gic gra de , a n d t he n u m ber of pri or pr o gressi o ns will be s u m marize d b y 
treat me nt ar m a n d o verall. N u m ber of pri or pr o gressi o ns will be deri ve d fr o m pri or s yste mic  
t hera p y, pri or ra diati o n t hera p y, a n d pri or s ur ger y c ollecte d o n t he C R F. Disease c haracteristics 
will als o be liste d.  
 
5. 3.   
C O N C O MI T A N T M E DI C A TI O N S  
All me dicati o n ver bati m ter ms c ollecte d will be c o de d t o A nat o mical T hera pe utic Classificati o n 
( A T C) a n d preferre d ter m ( P T ) usi n g t he W H O -D D Versi o n Se p 2 0 1 7.  
 
C o nc o mita nt me dicati o ns , i ncl u di n g be vaciz u ma b a n d de xa met has o ne, will be s u m marize d b y 
prese nti n g t he n u m ber a n d perce nta ge of partici pa nt s b y P T a n d A T C. Partici pa nt s ta ki n g t he sa me 
me dicati o n m ulti ple ti mes will o nl y be c o u nte d o nce f or t hat P T or A T C. Eac h s u m mar y will be 
or dere d b y desce n di n g or der of i nci de nce of A T C class a n d P T wit hi n eac h A T C class.  
 
T he n u m ber of partici pa nt s w h o recei ve be vaciz u ma b will be ta b ulate d al o n g wit h t he n u m ber of 
d oses a d mi nistere d  a n d d ose le vels recei ve d . C u m ulati ve act ual d ose will be s u m marize d. A 
partici pa nt’s be vaciz u ma b a d mi nistrati o n rec or d will be i ncl u de d if it occ urre d after cat heter 
place me nt a n d pri or t o t he partici pa nt’s  Wee k 5 2 or e n d of st u d y/last c o ntact date, w hic he ver 
occ urs f irst. If a partici pa nt has be vaciz u ma b liste d as a p ost st u d y s yste mic m o n o t hera p y rec or d, 
t his data will be i ncl u de d i n t he a nal ysis if t he start a n d st o p dates occ ur pri or t o a n y ot her t y pe of 
s u bse q ue nt a ntica ncer t hera p y (e. g. l o m usti ne, pe m br oliz u ma b,  iri n oteca n, ni v ol u ma b, car b o plati n, 
etc.). 
 


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 4  
2 7 J ul y 2 0 2 2  
 
T he n u m ber of partici pa nt s w h o recei ve de xa met has o ne will be ta b ulate d. T he da ys o n 
de xa met has o ne, c u m ulati ve act ual d ose, a n d a vera ge dail y d ose  will als o be s u m marize d. E x p os ure 
will o nl y be calc ulate d fr o m cat heter place me nt t o Wee k 5 2  or u ntil  t he partici pa nt’s e n d of 
st u d y/last c o ntact date, w hic he ver occ urs first. 
 
5. 4.   
B R AI N S U R G E R Y, R A DI O T H E R A P Y A N D S Y S T E MI C T H E R A P Y  
Brai n s ur ger y data will be liste d. T he n u m ber a n d perce nta ge of partici pa nt s wit h pri or brai n 
s ur ger y will be s u m marize d; data t o be i ncl u de d i n t he s u m mar y are e xte nt of resecti o n, hist ol o gic 
dia g n osis, C N S site, a n d C N S si de.  
 
T he pri or a n d s u bse q ue nt ra di ot hera p y will be liste d. T he n u m ber a n d perce nta ge of partici pa nt s 
wit h pri or ra di ot hera p y will be s u m marize d; data t o be i ncl u de d i n t he s u m mar y are C N S site, 
ra diati o n t hera p y t y pe, t otal d ose deli vere d, a n d treat me nt res p o nse. If a partici pa nt  e x perie nces 
m ore t ha n o ne pri or ra di ot hera p y, t he w orst -case will be use d f or n u merical s u m maries a n d all 
cases will be prese nte d f or cate g orical s u m maries. A partici pa nt  will o nl y be i ncl u de d i n a si n gle 
cate g or y o nce. 
 
All ver bati m ter ms c ollecte d of s u bse q ue nt s yste mic t hera p y will be c o de d t o A nat o mical 
T hera pe utic Classificati o n ( A T C) a n d P T usi n g t he W H O -D D Versi o n Se p 2 0 1 7.  
 
T he  pri or s yste mic t hera p y will be s u m marize d b y prese nti n g t he n u m ber a n d perce nta ge of 
partici pa nt s b y P T a n d A T C. Partici pa nt s ta ki n g t he sa me me dicati o n m ultiple ti mes will o nl y be 
c o u nte d o nce f or t hat P T or A T C. Eac h s u m mar y will be or dere d b y desce n di n g or der of i nci de nce 
of A T C class a n d P T wit hi n eac h A T C class. A d diti o nall y, t he t otal n u m ber of c ycles will be 
s u m marize d. If a partici pa nt  e x perie nces m ore t ha n o ne pri or s yste mic t hera p y, t he w orst-case will 
be use d f or n u merical s u m maries a n d all cases will be prese nte d f or cate g orical s u m maries. A 
partici pa nt  will o nl y be i ncl u de d i n a si n gle cate g or y o nce. All pri or a n d s u bse q ue nt s yste mic 
t hera pies will be prese nte d i n a partici pa nt  listi n g. 
 
5. 5.   
TI S S U E BI O M A R K E R S  
Tiss ue bi o mar ker a n d c ore bi o ps y data will be liste d. T he f oll o wi n g i nf or mati o n will be 
s u m marize d f or t he s u bject’s m ost rece nt visit pri or t o i nitiati o n of st u d y dr u g: 
• 
E G F R I H C  
• 
E G F R vIII I H C  
• 
M G M T I H C  
• 
M G M T pr o m oter met h ylati o n  
• 
I D H 1 R 1 3 2 H  
• 
I D H 1 m olec ular dia g n ostics 
• 
I D H 1 m utati o n t y pe 
• 
I D H 2 m olec ular dia g n ostics 


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 5  
2 7 J ul y 2 0 2 2  
 
• 
I D H 2 m utati o n t y pe 
• 
T E R T m olec ular dia g n ostics  
• 
T E R T m utati o n t y pe  
• 
P V R I H C  
 
5. 6.   
E X P O S U R E  
T he n u m ber of partici pa nt s w h o recei ve d st u d y dr u g a n d t otal d ose recei ve d will be s u m marize d.  
T he n u m ber of partici pa nt s w h o di d n ot recei ve o ne c ycle of l o m usti ne at t he re q uire d d ose le vel 
will be calc ulate d a n d t he reas o n f or n ot recei vi n g l o m usti ne as re q uire d will be s u m marize d f or 
t h ose ra n d o mize d t o t he l o m usti ne ar m pri or t o pr ot oc ol versi o n 7. 
 
5. 7.   
E F FI C A C Y  
5. 7. 1.   
Pri m ar y Effic ac y E n d p oi nt s 
T he pri mar y efficac y e n d p oi nts are O R R a n d D O R. O R R is defi ne d as t he pr o p orti o n of 
partici pa nt s ac hie vi n g C R or P R base d o n i R A N O criteria. D O R is defi ne d as t he ti me fr o m C R or 
P R u ntil c o nfir me d P D.  
 
5. 7. 1. 1.   
St ate me nt of  Esti m a n d  
T he p o p ul ati o n f or t he tri al  is defi ne d t hr o u g h a p pr o priate i ncl usi o n/e xcl usi o n criteria t o reflect 
t he tar gete d partici pa nt  p o p ulati o n f or a p pr o val. T he a nal ysis p o p ulati o n is base d o n t he F A S set. 
 
T he tre at me nts of i nterest are lera p olt ure v or lera p olt ure v + l o m usti ne.  
 
T he v ari a b le of i nterest f or O R R is t he bi nar y res p o nse val ue f or a partici pa nt . F or D O R , t he 
varia bles of i nterest are t he ti me fr o m first res p o nse t o pr o gressi o n/ deat h/ce ns ori n g, a n d a bi nar y 
ce ns ori n g val ue . 
 
T he a bilit y t o e val uate treat me nt effect usi n g t he var ia bles ma y be i m pacte d b y i nterc urre nt 
e ve nts  (I C Es). Deat h, use of a d diti o nal ca ncer treat me nts, a n d pre mat ure disc o nti n uati o n of st u d y 
ma y all i m pact t he i nter pretati o n of treat me nt effect.  F or O R R, a c o m p osite strate g y will be use d t o 
a d dress i nterc urre nt e ve nts (I C Es) of p ote ntial deat h, st u d y disc o nti n uati o ns, a n d start of a d diti o nal 
ca ncer treat me nts , mea ni n g occ urre nce of a n y of t hese e ve nts pri or t o a partici pa nt  ac hie vi n g C R or 
P R will mea n t he partici pa nt  is c o nsi dere d a n o n-res p o n der. D O R will use a c o m p osite strate g y as 
well, treati n g deat h as a n e ve nt t hat e n ds res p o nse, a n d st u d y  disc o nti n uati o ns or t he start of 
a d diti o nal ca ncer treat me nts  me dicati o ns will be ce ns ore d u n der t he strate g y . 
 
T he p o p ul ati o n le vel s u m m ar y me as ures  are t he O R R a n d t he  Ka pla n Meier esti mate d me dia n 
D O R , a n d ass ociate d c o nfi de nce i nter vals i n eac h treat me nt gr o u p. 
 


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 6  
2 7 J ul y 2 0 2 2  
 
5. 7. 2.   
Pri m ar y Effic ac y A n al ysis  
T he n u m ber of partici pa nt s i n eac h cate g or y of best o verall res p o nse ( C R, P R, S D, P D , 
i m m u n ores p o nse, i m m u n o pr o gressi o n, n o n -e val ua ble ( N E )), O R R, a n d DC R  will be s u m marize d.  
O R R a n d D C R al o n g wit h t heir ass ociate d e xact  9 5 % t w o-si de d c o nfi de nce i nter vals  ( CIs) usi n g 
Cl o p per Pears o n met h o d will be c o m p ute d wit hi n eac h treat me nt gr o u p . 
 
T he n u m ber of partici pa nt s wit h disease pr o gressi o n or deat h a n d t he n u m ber of ce ns ore d 
partici pa nt s will be s u m marize d. D O R will be s u m marize d usi n g Ka pla n-Meier met h o d s, a n d t he 
descri pti ve statistics of me dia n, 2 5 % a n d 7 5 % perce ntiles al o n g wit h t heir 9 5 % CIs will be 
calc ulate d.  T he Ka pla n -Meier s ur vi val c ur ve will als o be pl otte d.  
 
S u p p orti ve data listi n gs will als o be pr o vi de d.  
 
5. 7. 3.   
Sec o n d ar y Effic ac y  E n d p oi nts  
T he s ec o n dar y efficac y e n d p oi nts  f or t he st u d y are: 
• 
O verall s ur vi val (s pecificall y la n d ma r k s ur vi val) 
• 
Disease c o ntr ol rate  
 
5. 7. 4.   
Sec o n d ar y Effic ac y A n al ysis  
O S , i ncl u di n g la n d mar k s ur vi val rates (f oc usi n g at ≥ m o nt h  3 6) , will be s u m marize d usi n g Ka pla n -
Meier met h o d  t o esti mate t he me dia n, 2 5 % a n d 7 5 % perce ntiles al o n g wit h t heir 9 5 % CIs.  
 
I n a d ditio n t o t he q uartile s u m mar y fr o m Ka pla n -Meier met h o d, Ka pla n -Meier esti mates will be 
pr o vi de d f or t he s ur vi val rates at 1 2, 2 4, a n d 3 6 m o nt hs  al o n g wit h t heir 9 5 % CIs  f or OS . 
 
A nal ysis of D C R will be c o n d ucte d i n a si milar ma n ner  t o O R R i n Secti o n 5. 7 . 2. 
 
5. 8.   
S A F E T Y  
Val ues f or all safet y varia bles will be liste d b y partici pa nt  a n d visit  (as a p plica ble). Safet y 
s u m maries b y visit will use sc he d ule d visits u p t o Wee k 5 2. 
 
5. 8. 1.   
A d verse E ve nts  
A d verse e ve nts will be ma p pe d t o a Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) 
versi o n 2 0. 1 b y s yste m or ga n class  a n d preferre d ter m. If a partici pa nt  e x perie nces m ulti ple e ve nts 
t hat ma p t o a si n gle preferre d ter m, t he greatest se verit y a n d str o n gest assess me nt of relati o n t o a 
st u d y dr u g  will be assi g ne d t o t he preferre d ter m f or t he a p pr o priate s u m maries. A Es will be 
c ollecte d fr o m Da y 1  t hr o u g h 3 0 da ys after t he partici pa nt  is c o nsi dere d off-st u d y. A E se verit y will 
be assesse d acc or di n g t o t he C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) versi o n 
4. 0 3. If C T C A E gra di n g d oes n ot e xist f or a n A E, t he se verit y of t he A E will be gra de d as mil d ( 1), 
m o derate ( 2), se vere ( 3), life -t hreate ni n g ( 4), or fatal ( 5). 


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 7  
2 7 J ul y 2 0 2 2  
 
 
T he n u m ber of partici pa nt s f or t he f oll o wi n g gr o u ps will be s u m marize d b y treat me nt gr o u p a n d 
o verall : 
• 
A n y t reat me nt-e mer ge nt A E ( T E A E)  
• 
A n y treat me nt -e mer ge nt seri o us A Es ( T E S A Es)  
• 
A n y treat me nt -e mer ge nt A E SIs  
• 
A n y T E A E relate d t o a st u d y  dr u g  or cat heter  
• 
A n y T E S A E relate d t o a st u d y dr u g or cat heter 
• 
A n y T E A E wit h gra de ≥ 3  
• 
A n y T E A E wit h gra de ≥ 3  relate d t o st u d y dr u g or cat heter  
 
T he occ urre nce of T E A Es  a n d T E A Es relate d t o st u d y dr u g or cat heter will be s u m marize d b y 
preferre d ter m, s yste m or ga n class, a n d se verit y. S h o ul d a n e ve nt ha ve a m issi n g se verit y or 
relati o ns hi p, it will be classifie d as ha vi n g t he hi g hest se verit y a n d/ or str o n gest relati o ns hi p t o 
st u d y me dicati o n. Se parate s u m maries of T E S A Es, T E S A Es relate d t o st u d y dr u g or cat heter, 
treat me nt-e mer ge nt A E SIs , T E A Es  wit h gra de ≥ 3 , a n d T E A Es wit h gra de ≥ 3 relate d t o a st u d y 
dr u g  or cat heter  will be ge nerate d  b y preferre d ter m a n d s yste m or ga n class . All a d verse e ve nts 
re p orte d will be liste d f or i n di vi d ual partici pa nt s s h o wi n g b ot h ver bati m a n d preferre d ter ms. All 
a d verse e ve nts t hat occ urre d pri or t o cat heter place me nt  wil l be e xcl u de d fr o m t he ta bles b ut will 
be i ncl u de d i n t he listi n gs.  
 
 Missi n g o nset dates will be i m p ute d as pre vi o usl y o utli ne d i n Secti o n 3. 2. 3. 2  as re q uire d t o 
deter mi ne treat me nt -e mer ge nt e ve nts.  
5. 8. 2.   
Cli nic al L a b or at or y Assess me nts  
T o xicities f or cli nical la bs will be c haracterize d acc or di n g t o  C T C A E v ersi o n 4. 0 3 ( w he n p ossi ble)  
a n d s hift i n gra de fr o m baseli ne t o t he w orst p ost-baseli ne val ue will be s u m marize d. B ot h 
sc he d ule d a n d u nsc he d ule d assess me nts will be use d t o i de ntif y t he w orst p ost -baseli ne val ues.  
 
T he f oll o wi n g cate g ories of a b n or mal he patic la b orat or y val ues will be e val uate d f or a n y  
occ urre nce a m o n g all p ost baseli ne assess me nts.  
• 
Ala ni ne A mi n otra nsferase  (A L T ) a n d/ or As partate A mi n otra nsferas e ( A S T ) >  3  x u p per li mit 
n or mal ( U L N) , A L P < 2 x  U L N, a n d T otal Bilir u bi n ≥ 2  x U L N  
• 
A S T > 3,  5,  8,  1 0, a n d 2 0  x U L N , a n d 5 x U L N f or m ore t ha n 5 wee ks 
• 
A L T > 3,  5,  8,  1 0, a n d 2 0  x U L N , a n d 5 x U L N f or m ore t ha n 5 wee ks 
• 
T otal Bilir u bi n >  1. 5 or ≥ 2  x U L N  
 
Listi n gs of all la b orat or y data wit h n or mal refere nce ra n ges, a n d C T C A E gra des ( w he n p ossi ble) 
will be pr o vi de d.  
 


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 8  
2 7 J ul y 2 0 2 2  
 
5. 8. 3.   
Vit al Si g ns  
F or vital si g n para meters (s yst olic bl o o d press ure, diast olic bl o o d press ure, heart rate, res pirat or y 
rate, b o d y te m perat ure, b o d y s urface area a n d wei g ht) t he o bser ve d val ues a n d c ha n ge fr o m 
basel i ne will be s u m marize d usi n g descri pti ve statistics at eac h visit. T he ma xi m u m p ost -baseli ne 
val ues a n d t he c ha n ge fr o m baseli ne will als o be s u m marize d.  
 
A listi n g of all vital si g n data will be pr o vi de d.  
 
5. 8. 4.   
K P S  
T he o bser ve d val ues a n d t he c ha n ge fr o m baseli ne i n t he Kar n ofs k y perf or ma nce stat us sc ore will 
be s u m marize d usi n g descri pti ve statistics at eac h visit b y treat me nt gr o u p.  T he ma xi m u m p ost -
baseli ne val ues a n d t he c ha n ge fr o m baseli ne will als o be s u m marize d.  
 
A listi n g of K P S data will be ge ner ate d. 
 
6.   
P R O T O C O L D E VI A TI O N S  
Pr ot oc ol de viati o n  s u m maries a n d listi n g are n ot c o vere d b y t his S A P b ut will be prese nte d i n t he 
cli nical st u d y re p ort. 
 
7.   
C H A N G E S I N T H E P L A N N E D A N A L Y S E S  
1.  T he i nteri m a nal ysis n ote d i n t he pr ot oc ol was n ot c o n d ucte d.  
2.  T he decisi o n t o st o p t he lera p olt ure v + l o m usti ne ar m was ma de pri or t o t he data base bei n g 
u p date d t o reflect t his c ha n ge. T h us, t he ra n d o mizati o n ar m i n Electr o nic Data Ca pt ure  (E D C ) 
is i nc orrect f or t he f oll o wi n g partici pa nt s: 
•  
1 0 6 8, 1 0 7 0, 1 0 7 3, 1 0 7 4, 1 0 7 8, 1 0 8 2, 1 0 8 3, 4 0 0 5, 4 0 0 8 s h o w as ra n d o mize d t o lera p olt ure v 
+ l o m usti ne  b ut  were  assi g ne d  t o lera p olt ure v o nl y  
T he treat me nt ar m will be u p date d t o reflect t he c ha n ges f or a nal ysis p ur p oses.  
3.  Partici pa nts 1 0 1 2 a n d 1 0 2 0 were ra n d o mize d t o lera p olt ure v + l o m usti ne a n d partici pa nts 1 0 3 3 
a n d 1 0 5 8 were ra n d o mize d t o lera p olt ure v. H o we ver, t hese partici pa nts scree n faile d pri or t o 
treat me nt. T hese s u bjects will be c o nsi dere d scree n fail ures f or t he a nal ysis . 
4.  1 0 9 8 was ra n d o mize d t o lera p olt ure v b ut t he partici pa nt’s ra n d o mizati o n a n d treat me nt 
assi g n me nt were n ot c ollecte d i n err or. T he decisi o n t o st o p t he lera p olt ure v + l o m usti ne ar m 
was ma de pri or t o 1 0 9 8’s e nr oll me nt; t h us, t he assi g ne d ar m is lera p olt ure v wit h t he date t he 
i n vesti gator  si g ne d off o n t he partici pa nt  as eli gi ble (2 1 -N o v -2 0 1 9 ) will be use d as t he 
ra n d o mizati o n date. 
5.  C o m paris o n t o t he e xter nal c o ntr ol will n ot be d o ne f or a n y efficac y a nal yses. Acc or di n gl y, t he 
differe nces bet wee n t he t w o gr o u ps wit h res pect t o de m o gra p hi cs ( Secti o n 1 4. 6 of t he pr ot oc ol) 
will n ot be perf or me d.  


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 9  
2 7 J ul y 2 0 2 2  
 
6.  Da y 0  is t he earliest da y t hat st u d y dr u g is i nitiate d b ut will be desi g nate d as Da y 1 base d o n 
i m ple me ntati o n sta n dar ds f or t he a nal ysis. 
7.  Ce ntral i ma gi n g re vie w was n ot c o m plete d a n d, t heref ore, res ults fr o m t his will n ot be 
prese nte d.  
8.  Safet y s u m maries f or eac h c o h ort ra n d o mize d pri or t o pr ot oc ol versi o n 7 a n d well as t h ose 
retreate d wit h lera p olt ure v ( Secti o n 1 4. 6 of t he pr ot oc ol) will n ot be d o ne. 
9.  Safet y s u m maries f or e ve nts relate d t o be vaciz u ma b or c ortic oster oi ds will n ot be d o ne.  
1 0.  T he e x pl orat or y a nal yses descri be d i n Secti o n 1 4. 7 of t he pr ot oc ol will n ot be d o ne.  
8.   
R E VI SI O N HI S T O R Y  
D ate   
Re visi o n  
R ati o n ale  
2 7 J ul y 2 0 2 2  
A d de d deri vati o n of i nc o m plete/ missi n g 
dates f or de xa met has o ne use  
T o all o w f or acc urate 
de xa met has o ne s u m mar y 
calc ulati o ns of da ys o n dr u g, 
c u m ulati ve d ose, a n d a vera ge dail y 
d ose.  
U p date d a nal ysis of de xa met has o ne   
T o u p date e x p os ure s u m maries 
i ncl u de d i n t he a nal ysis base d o n 
t he data c ollecte d. 
U p date d a nal ysis of be vaciz u ma b   
T o u p date e x p os ure s u m maries 
i ncl u de d i n t he a nal ysis base d o n 
t he data c ollecte d. 
C ha n ge d I T T t o f ull a nal ysis set   
T o create a p o p ulati o n of s u bjects 
w h o were ra n d o mize d , ha d a 
cat heter place d , a n d recei ve d t he 
i nitial d ose of lera p olt ure v. 
C ha n ge d p o p ulati o n use d f or t he efficac y 
a nal ysis a n d ot her a d diti o nal s u m maries  
T o o nl y i ncl u de s u bjects t hat were 
i n t he F A S p o p ulati o n i n efficac y 
a n d select s u m maries.  
U p date d partici pa nt i nf or mati o n i n t he 
c ha n ges i n pla n ne d a nal ysis s ecti o n 
U p date d/a d de d partici pa nt 
i nf or mati o n t o clarif y 
ra n d o mizati o n/assi g ne d treat me nt 
a n d t he treat me nt recei ve d.  
A d de d clarit y t o defi niti o n of d urati o n of 
res p o nse 
U p date d t o o nl y c o nsi der sca ns 
c ollecte d bef ore t he patie nt was 
c o nsi dere d off -st u d y 
A d de d clarit y t o defi niti o n of Baseli ne   
U p date d t o c o nsi der rec or ds wit h 
missi n g ti me as p ost -Baseli ne  
U p date d a nal ysis of tiss ue bi o mar kers   
U p date d t o s pecif y t he rec or ds use d 
f or t he a nal ysis 
9.   
R E F E R E N C E S  


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 3 0  
2 7 J ul y 2 0 2 2  
 
1 0.   
P R O G R A M MI N G C O N V E N TI O N S  
•  
Pa ge orie ntati o n, mar gi ns, a n d f o nts : S u m mar y ta bles, listi n gs, a n d fi g ures will a p pear i n 
la n dsca pe orie ntati o n.  T here s h o ul d be a mi ni m u m of a 1. 0” b o u n dar y o n t he left a n d ri g ht 
e d ges. T he t o p a n d b ott o m mar gi ns are 1. 0” f or ta bles a n d listi n gs b ut ma y var y  f or fi g ures. 
O ut p ut s h o ul d be pri nte d i n C o urier Ne w wit h a p oi nt size of 8 .  Titles ma y be pri nte d usi n g a 
lar ger f o nt (e. g., Arial p oi nt size 1 0). 
•  
I de ntificati o n of a nal ysis p o p ulati o n: E ver y s u m mar y ta ble a n d fi g ure s h o ul d clearl y s pecif y 
t he a nal ysis p o p ulati o n bei n g s u m marize d.  Listi n gs will be pre pare d f or all partici pa nt s. 
•  
Gr o u p hea ders:  I n t he s u m mar y ta bles, t he gr o u p hea ders will i de ntif y t he s u m mar y gr o u p a n d 
t he sa m ple size for t he i n dicate d a nal ysis p o p ulati o n.  Of n ote, t he hea der’s sa m ple size d oes 
n ot necessaril y e q ual t he n u m ber of partici pa nt s s u m marize d wit hi n a n y gi ve n s u m mar y 
m o d ule; s o me partici pa nt s i n t he a nal ysis p o p ulati o n ma y ha ve missi n g val ues a n d t h us ma y 
n ot  be s u m marize d.  
•  
S u p pressi o n of perce nta ges c orres p o n di n g t o n ull cate g ories:  W he n c o u nt data are prese nte d as 
cate g or y fre q ue ncies a n d c orres p o n di n g perce nta ges, t he perce nt s h o ul d be s u p presse d w he n 
t he c o u nt is zer o t o dra w atte nti o n t o t he n o n -zer o c o u nts. 
•  
Prese ntati o n of sa m ple sizes:  S u m mar y m o d ules s h o ul d i n dicate, i n o ne wa y or a n ot her, t he 
n u m ber of partici pa nt s c o ntri b uti n g  t o t he s u m mar y statistics prese nte d i n a n y gi ve n s u m mar y 
m o d ule.  As me nti o ne d a b o ve, t his ma y be less t ha n t he n u m ber of part ici pa nts i n t he a nal ysis 
p o p ulati o n  d ue t o missi n g data . 
•  
I n t he q ua ntitati ve m o d ules descri bi n g c o nti n u o us varia bles (a n d t h us prese nti n g sa m ple 
size, mea ns, a n d sta n dar d de viati o ns), t he sa m ple size s h o ul d be t he n u m ber of n o n -
missi n g o bser vati o ns .  T he nu m ber of missi n g o bser vati o ns, if a n y, will be n ote d.  
•  
F or cate g orical varia bles t hat are prese nte d i n fre q ue nc y ta bles, t he m o d ule s h o ul d prese nt 
t he t otal c o u nt i n a d diti o n t o t he c o u nt i n eac h cate g or y.  Perce nta ges s h o ul d be calc ulate d 
usi n g t his t otal as t he de n o mi nat or, a n d t he perce nta ge c orres p o n di n g t o t he s u m itself (t hat 
is, 1 0 0 %) s h o ul d be prese nte d t o i n dicate clearl y t o a re vie wer t he met h o d of calc ulati o n.  
T he n u m ber of missi n g o bser vati o ns, if a n y, will be n ote d.  
•  
S orti n g:  Listi n gs will be s o rte d b y treat me nt gr o u p, partici pa nt  n u m ber a n d date, if a p plica ble.  
If a listi n g is s orte d i n a differe nt ma n ner, a f o ot n ote will i n dicate as s uc h.  
•  
Ge neral f or matti n g r ules:  R o u n di n g f or all varia bles will occ ur o nl y as t he last ste p, 
i m me diatel y pri or t o prese ntati o n i n listi n gs, ta bles, a n d fi g ures.  N o i nter me diate r o u n di n g will 
be perf or me d o n deri ve d varia bles.  T he sta n dar d r o u n di n g practice of r o u n di n g n u m bers 
e n di n g i n 0 -4 d o w n a n d n u m bers e n di n g i n 5 -9 u p will be e m pl o ye d.   
•  
N u merical Val ues:  T h e prese ntati o n of n u merical val ues will a d here t o t he f oll o wi n g 
g ui deli nes:  
•  
Ra w meas ure me nts will be re p orte d t o t he n u m ber of si g nifica nt di gits as ca pt ure d 
electr o nicall y or o n t he C R Fs.   


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 3 1  
2 7 J ul y 2 0 2 2  
 
•  
Sta n dar d de viati o ns will be re p orte d t o o ne deci mal place be y o n d  t he n u m ber of deci mal 
places t he ori gi nal para meter is prese nte d.  
•  
Mea ns will be re p orte d t o t he sa me n u m ber of si g nifica nt di gits as t he para meter.  
•  
Calc ulate d perce nta ges will be re p orte d wit h n o deci mals.  
•  
Dates will be f or matte d as D D M M M Y Y Y Y.  Partial d ates will be prese nte d o n data listi n gs as 
rec or de d o n C R Fs. 
•  
Ti me will be prese nte d acc or di n g t o t he 2 4 -h o ur cl oc k ( H H :M M).  


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 3 2  
2 7 J ul y 2 0 2 2  
 
1 1.   
P R O P O S E D  T A B L E S, LI S TI N G S, A N D FI G U R E S  
 
S u m m ar y T a bles  
Acc o u nt a bilit y a n d B aseli ne C h ar acteristics  
1 4. 1. 1 . 1  
Partici pa nt  Dis p ositi o n , All E nr olle d Partici pa nt s 
1 4. 1. 2 . 1  
De m o gra p hics a n d Baseli ne C haracteristics , F ull A nal ysis Set   
1 4. 1. 3 . 1  
Disease C haracteristics , F ull A nal ysis Set   
1 4. 1. 3. 2   
S u m mar y of Pri or A nti -Ca ncer T hera p y , F ull A nal ysis Set   
1 4. 1. 3. 3   
S u m mar y of Tiss ue Bi o mar kers, F ull A nal ysis Set   
1 4. 1. 4 . 1  
C o nc o mita nt Me dicati o ns , F ull A nal ysis  Set  
1 4. 1. 4. 2   
Be vaciz u ma b A d mi nistrati o n, F ull A nal ysis  Set  
1 4. 1. 4. 3   
De xa met has o ne Use , F ull A nal ysis  Set   
1 4. 1. 5 .1   
S u m mar y of St u d y Dr u g E x p os ure , Safet y Set  
 
Effic ac y  
1 4. 2 . 1. 1  
S u m mar y of Best O verall T u m or Res p o nse  a n d D urati o n of Res p o nse , F ull 
A nal ysis  Set  
1 4. 2. 2 . 1  
S u m mar y of O verall S ur vi val , F ull A nal ysis  Set  
 
S afet y  
1 4. 3. 1. 1   
O verall S u m mar y of Treat me nt -E mer ge nt A d verse E ve nts , Safet y Set  
1 4. 3. 1 .2   
Treat me nt -E mer ge nt A d verse E ve nts b y S yste m Or ga n Class, Preferre d  
  
  
Ter m, a n d Greatest Se verit y , Safet y Set  
1 4. 3. 1. 3   
Treat me nt -E mer ge nt A d verse E ve nts Relate d t o St u d y Dr u g or Cat heter  b y S yste m 
Or ga n Class , Preferre d Ter m, a n d Greatest Se verit y, Safet y Set  
1 4. 3. 1. 4   
Treat me nt -E mer ge nt Seri o us A d verse E ve nts b y S yste m Or ga n Class a n d  
  
  
Preferre d Ter m , Safet y Set  
1 4. 3. 1. 5   
Treat me nt -E mer ge nt Seri o us A d verse E ve nts Relate d t o St u d y Dr u g or Cat heter  b y 
S yste m Or ga n Class a n d Preferre d Ter m, S afet y Set 
1 4. 3. 1. 6   
Treat me nt -E mer ge nt A d verse E ve nts of S pecial I nterest b y S yste m Or ga n Class  
a n d Preferre d Ter m, Safet y Set  
1 4. 3. 1. 7   
Treat me nt -E mer ge nt A d verse E ve nts wit h Gra de ≥ 3  b y S yste m Or ga n Class a n d 
Preferre d Ter m , Safet y Set  
1 4. 3. 1. 8   
Treat me nt -E mer ge nt A d verse E ve nts wit h Gra de ≥ 3  a n d Relate d t o St u d y Dr u g  or 
Cat heter  b y S yste m Or ga n Class a n d Preferre d Ter m, Safet y Set  
1 4. 3. 4 .1   
S u m mar y of Gra de S hifts i n La b orat or y A b n or malities –  He mat ol o g y, Safet y Set  
1 4. 3 .4 .2   
S u m mar y of Gra de S hifts i n La b orat or y A b n or malities –  C he mistr y, Safet y Set  
1 4. 3. 4. 3   
N u m ber of Partici pa nt  wit h at Least O ne A L T, A S T, or T otal Bilir u bi n  A b o ve 
U p per Li mi t of t he N or mal Ra n ge P ost-Baseli ne , Safet y Set  
1 4. 3. 4. 4   
S u m mar y of Vital Si g ns b y Visit, Safet y Set  
1 4. 3. 4. 5   
S u m mar y of Kar n ofs k y Perf or ma nce Stat us Sc ore b y Visit, Safet y Set  
 
 
 


Istari O nc ol o g y I nc. 
Pr o 0 0 0 7 7 0 2 4  
Statistical A nal ysis Pla n  
Fi nal Versi o n 2. 0  
 
 
C O N FI D E N TI A L  
Pa ge 3 3  
2 7 J ul y 2 0 2 2  
 
S u m m ar y Fi g ures  
Effic ac y  
1 4. 2 .1 . 2  
D urati o n of Res p o nse  –  Ka pla n Meier C ur ve, F ull A nal ysis Set  
1 4. 2. 2 . 2  
O verall S ur vi val –  Ka pla n Meier C ur ve, F ull A nal ysis Set  
D at a Listi n gs  
1 6. 1. 7. 1   
Partici pa nt  E nr oll me nt  
1 6. 2. 1. 1   
Partici pa nt  Dis p ositi o n  
1 6. 2. 2. 1   
I ncl usi o n/ E xcl usi o n Criteria  
1 6. 2. 3. 1   
A nal ysis Sets  
1 6. 2. 4 . 1  
De m o gra p hics  a n d Baseli ne C haracteristics  
1 6. 2. 4. 2   
Me dical Hist or y  
1 6. 2. 4. 3   
Disease Stat us  
1 6. 2. 4. 4 . 1 Pri or Ra diati o n T hera p y  
1 6. 2. 4. 4. 2  P ost -St u d y Ra diati o n T hera p y  
1 6. 2. 4. 5 . 1 Pri or S yste mic T hera p y  
1 6. 2. 4. 5. 2  P ost -St u d y S yste mic T hera p y  
1 6. 2. 4. 6 . 1 Pri or a n d C o nc o mita nt Me dicati o ns  
1 6. 2. 4. 7. 1  Tiss ue Bi o mar kers a n d C ore Bi o psies  
1 6. 2. 5. 1. 1  L era p olt ure v  I nf usi o n 
1 6. 2. 5. 1. 2  L o m usti ne A d mi nistrati o n  
1 6. 2. 5. 1. 3  Cat heter Place me nt  
1 6. 2. 6 . 1  
Lesi o n Descri pti o n  
1 6. 2. 6. 2   
Lesi o n Assess me nt  
1 6. 2. 6. 3   
Lesi o n Res p o nse  
1 6. 2. 6. 4   
Brai n S ur ger y  
1 6. 2. 6. 5   
F oll o w -U p  
1 6. 2. 6. 6   
O verall S ur vi val  
1 6. 2. 7. 1       A d verse E ve nts  
1 6. 2. 7. 2   
Deat h  
1 6. 2. 8 . 1  
La b orat or y Val ues –  He mat ol o g y  
1 6. 2. 8. 2   
La b orat or y Val ues –  C he mistr y  
1 6. 2. 8. 3   
La b orat or y Val ues –  C oa g ulati o n  
1 6. 2. 8. 4   
A nti -P oli o Vir us Titer  
1 6. 2. 8. 5   
C O VI D -1 9 I m pact  
1 6. 2. 9. 1   
Vital Si g ns  
1 6. 2. 1 0. 1  
Kar n ofs k y Perf or ma nce Stat us