A Single-Arm, Open-Label, Compassionate Use Study of VSV-02 Administered Intravenously and Intratumorally in Patients With Advanced Solid Tumors
Phase: PHASE1
Conditions: Advanced Solid Tumor, Melanoma, Breast Cancer, Lung Cancer, Cancer Treatment, Immunotherapy
Sponsor: The First Affiliated Hospital of Xinxiang Medical College

Protocol number: VSV-02A0 1tqyy
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Clinical Trial Protocol
An Open-Label, Single-Arm Compassionate Use Study of VSV-02
Given by Intravenous and Intratumoral Injection in Patients with
Advanced Solid Tumors
Protocol Number:
VSV-02A01tqyy
Version Number:
v 1.0
Version Date:
June 25, 2025
Principal Investigator:
Liuzhong Yang
Group leader unit:
The First Affiliated Hospital
of Xinxiang Medical University
Sponsor:
Shanghai Rong Rui
Pharmaceutical Technology
Co., Ltd.
Sponsor:
Shanghai Rong Rui
Pharmaceutical Technology
Co., Ltd.

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List of Abbreviations
Abbreviations
and Terms
Full name in English
AE
Adverse Event
ADA
Anti-drug Antibody
ADR
Adverse Drug Reaction
ALT
Alanine Aminotransferase
ALP
Alkaline Phosphatase
ANC
Absolute Neutrophil Count
APTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
CCr
Creatinine Clearance
CR
Complete Response
CRF
Case Report Form
CRO
Contract Research Organization
CRS
Cytokine Release Syndrome
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CVA
Cerebralvascular Accident
DCR
Disease Control Rate
DLT
Dose Limited Toxicity
DMP
Data Management Plan
DNA
Deoxyribonucleic Acid
DoR
Duration of Response
ECOG
Eastern Cooperative Oncology Group
ECG
Electrocardiogram
EDC
Electronic Data Capture System
FAS
Full Analyse Set
FIB
Fibrinogen
GCP
Good Clinical Practice
HBcAb
Hepatitis B Core Antibody
HBsAg
Hepatitis B Surface Antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HED
Human Equivalent Dose
HIV
Human Immunodeficiency Virus

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HNSTD
Highest Non-severely Toxic Dose
HSV
Herpes Simplex Virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IL
Interleukin
INR
International Normalized Ratio
IFN-γ
Interferon-γ
irAE
Immune-Related Adverse Events
IRB
Institutional Review Board
ITT
Investigator-initiated Trial
LVEF
Left Ventricular Ejection Fraction
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MTD
Maximum Tolerated Dose
NY-ESO-1
New York esophageal squamous cell carcinoma 1
NYHA
New York Heart Association
ORR
Objective Response Rate
OS
Overall Survival
OV
Oncolytic Viruses
PD-L1
Programmed cell death 1 ligand 1
PFS
Progression-Free-Survival
PFU
Plaque Forming Unit
PPS
Per Protocol Set
PR
Partial response
PT
Prothrombin Time
PT
Preferred Terms
QD
Quaque Die
qPCR
Quantitative PCR Detecting System
RECIST
Response Evaluation Criteria in Solid Tumours
RNA
Ribonucleic Acid
RP2D
Recommended Phase 2 Dose
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Stable Disease
SMC
Safety Monitoring Committee

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SOC
System Organ Classification
SOP
Standard Operation Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SS
Safety Analysis set
TAA
Tumor-associated Antigen
TBIL
Total bilirubin
TCID50
50% Tissue Culture Infective Dose
TNF-α
Tumor Necrosis Factor
TPO
Thrombopoietin
TIA
Transient Ischemic Attack
TLS
Tumor Lysis Syndrome
ULN
upper limit of normal
VSV
Vesicular stomatitis virus
WBC
white blood cell

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Catalog
Catalog.................................................................................................................................................... 5
Program Summary.................................................................................................................................. 6
1
Introduction.....................................................................................................................................14
2
Trial Objectives and Endpoints.......................................................................................................28
3
Experimental design........................................................................................................................28
4
Study Population.............................................................................................................................33
5
Research Intervention..................................................................................................................... 39
6
Study Steps......................................................................................................................................45
7
Study Evaluation.............................................................................................................................49
8
Adverse Events and Serious Adverse Events................................................................................. 54
9
Statistical Considerations................................................................................................................69
10 Data Processing and Record Keeping.............................................................................................72
11 Code of Ethics and Informed Consen............................................................................................. 74
12 Quality Assurance and Quality Control..........................................................................................76
13 References.......................................................................................................................................78

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Program Summary
Summary
Program Number
VSV-02A01tqyy
Program Name
An Open-Label, Single-Arm Compassionate Use Study of VSV-02 Given by Intravenous
and Intratumoral Injection in Patients with Advanced Solid Tumors
Version number/date
v <1.0 >, < June 25, 2025 >
Trial staging
Phase I Clinical Trial
Sponsor
Shanghai Rong Rui Pharmaceutical Technology Co., Ltd.
Principal
Investigator
Liuzhong Yang
Clinical Trial
Organization
The First Affiliated Hospital of Xinxiang Medical University
Trial Objectives and
Endpoints
Primary objective
Primary endpoint

To evaluate the preliminary efficacy
of intravenous and intratumoral
administration of VSV-02 Injection
in subjects with advanced solid
tumors;

Objective remission rate (ORR), disease
control rate (DCR), duration of response
(DoR), progression-free survival (PFS),
and overall survival (OS);
Secondary endpoints
Secondary Endpoints

To evaluate the safety of VSV-02
Injection administered intravenously
and intratumorally in subjects with
advanced solid tumors.

Incidence and characterization of adverse
events (AE);

Changes in safety indicators such as
laboratory findings, physical examination,
electrocardiogram and vital signs
compared to baseline;
Experimental
design.
This study is an open, single-arm, dose-escalation clinical study designed to evaluate
the preliminary efficacy and safety of VSV-02 Injection intravenously and intratumorally in
subjects with advanced solid tumors for compassionate use in patients lacking effective
treatment modalities.
Patients eligible for enrollment will be screened and given a fixed dose: 3×10(1)
(0)PFU/mL (it.) + 3×1011PFU (iv.); systematic safety observations will be made within 6
weeks of the first dose, and if no DLTs are observed in three patients, the dose will be
determined to be the Maximum Tolerated Dose (MTD) and the Recommended Phase II Dose
(RP2D). If DLT is observed in 1 patient, 3 additional subjects will be added to the cohort, If
DLT is observed in ≥2 patients, the new cohort will be added at a lower dose as
recommended by the SMC (recommended dose is: 3×1010PFU/mL(it.) + 3×1010PFU (iv.)).
Upon completion of the dose group, the SMC assessed whether to newly continue the dose
escalation based on outcome assessment.
After the first dose, subjects entered a 28-day DLT observation period, and if no DLT
occurred during this period, they continued to be given subsequent treatment.
The study included a screening period, a treatment period and a follow-up period.
Screening period:was from the date the subject signed the informed consent form to the
time of the first dose (D-28 to D-1).
TREATMENT PERIOD: Screening-eligible subjects were administered starting on
Week 1 Day 1 (W1D1), with treatment cycles every 3 weeks, with intravenous and
intratumoral injections administered on the same day, and adjusted as necessary to account
for the patient's condition. Subjects were administered according to the dose group in
which they were placed until disease progression, intolerable toxicity in the subject,
withdrawal of informed consent by the subject, death of the subject, loss to follow-up,
termination of treatment as deemed by the investigator to be in the best interest of the
patient, or the study drug had been administered for the full 6 cycle, whichever occurred
earliest. Some subjects may experience transient tumor growth and pseudo-progression
during the first few months after initiation of immunotherapy, followed by disease remission.
After the first imaging progression in a subject, as determined by the investigator according

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to RECIST 1.1 criteria, subjects will be allowed to continue treatment with VSV-02 injection
if the investigator determines that the subject is in a clinically stable state and it is believed
that there may be a clinical benefit to continue treating the subject. If the imaging assessment
shows disease progression as determined according to RECIST 1.1 and there is no clinical
deterioration, another tumor assessment should be performed at least 4 weeks later to
confirm disease progression according to iRECIST. Clinical stability is defined as the
absence of clinically significant signs and symptoms suggestive of disease progression
(including abnormal laboratory test values), no reduction in Eastern Cooperative Oncology
Group (ECOG) Physical Status Score, no rapid disease progression, and the absence of
progressive tumors (e.g., spinal cord compression) at important anatomical sites that would
require other urgent medical intervention. Subjects judged to be clinically unstable should
terminate trial treatment after the first imaging disease progression evaluated by the
investigator and without the need for repeat imaging to confirm disease progression.
Follow-up Period: The follow-up period consists of a safety follow-up and a survival
follow-up. If a subject terminates treatment for any reason, he/she is required to return to the
study center for a safety follow-up within 28 days (±7 days) of the last dose. Subjects then
enter a survival follow-up period, which occurs every 12 weeks until the subject withdraws
informed consent, dies, loses the visit, receives another antitumor therapy other than that
specified in the protocol, or the study ends, whichever occurs earliest. After subjects have
completed 6 cycles of dosing, if the investigator judges that subjects may still benefit from
continuing treatment with VSV-02 Injection, each patient should be consulted, and if the
subject requests to continue treatment, he or she may apply to continue treatment, but must
sign a separate informed consent form, the specific content of which should be based on the
actual condition of the patient, and formulated after communication with the investigator.
Dose-Limiting
Toxicity (DLT)
Sympathetic to patients on the drug, it is not necessary to observe the emergence of
DLT. In the event of an adverse reaction requiring treatment in clinical judgment,
medication may be given at any time and discontinued at any time if necessary.
Trial Population
Inclusion Criteria:
Subjects need to meet the following enrollment criteria to be enrolled in this trial:
1.
Voluntarily sign an informed consent form, understand the study and be willing to
follow the protocol and complete all trial procedures;
2.
Age ≥18 years at the time of signing the ICF and gender.
3.
Patients with advanced solid tumors, including but not limited to: melanoma, squamous
cell carcinoma of the head and neck, cervical cancer, osteosarcoma, nasopharyngeal
carcinoma, breast cancer, lung cancer, colorectal cancer, hepatocellular carcinoma,
gastric carcinoma, etc., that have been diagnosed by histologic/cytologic examination
of the primary and/or metastatic lesion pathology.
4.
Patients who have failed standard therapy and lack standard therapy in the endline or
are not candidates for standard therapy for medical reasons. Patients need to have
progressed on at least two standard therapies (including but not limited to targeted
therapies). For example, subjects with metastatic or unresectable advanced melanoma
will need to have failed standard therapy such as PD-1 antibody (or BRAF and MEK
inhibitors if carrying a BRAF mutation); subjects with recurrent or metastatic advanced
squamous cell carcinoma of the head and neck will need to have failed standard therapy
such as anti-PD-1 monoclonal antibody as well as platinum-containing chemotherapy;
and patients with recurrent or metastatic osteosarcoma will need to have failed standard
of care with chemotherapeutic agents, including high-dose methotrexate, doxorubicin,
cisplatin, isocyclophosphamide, etc.); colorectal cancer patients who have received
standard chemotherapy with fluoropyrimidines, oxaliplatin, bevacizumab, and
irinotecan, wild-type KRAS patients with anti-EGFR therapy, and patients with high
microsatellite instability who have received at least one immune checkpoint inhibitor;
and breast cancer patients (including HR positive, HER2 + and triple-negative breast
cancer), need to have received at least 2 prior treatments, which should include
paclitaxel and/or anthracycline therapy, as appropriate, and an approved checkpoint
inhibitor.
5.
In principle, subjects have a lesion judged measurable according to RECIST 1.1 criteria,
i.e., a non-lymph node lesion with a long diameter of ≥10 mm and a lymph node lesion

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with a short diameter of ≥15 mm based on CT or MRI. and need to have an injectable
tumor lesion, including a superficial lesion, as well as a deeper lesion that can be
injected under ultrasound/CT/ or endoscopic guidance.
6.
Subjects with an ECOG physical status score of 0-2 and an expected survival of not less
than 12 weeks.
7.
Adequate organ and hematopoietic function, if the following criteria are not met,
safety may be judged on a clinical basis:

Absolute Neutrophil Count (ANC) ≥1.5×109/L;

Platelets ≥75×109/L (no platelet transfusion therapy or thrombopoietin (TPO)
therapy within 2 weeks prior to first dose);

Hemoglobin ≥90 g/L (no blood transfusion within 2 weeks);

Serum creatinine ≤1.5×upper limit of normal (ULN) or endogenous creatinine
clearance (CCr) ≥50mL/min;

Glutamine transaminase (AST) and alanine transaminase (ALT) ≤3.0 × ULN; AST
and ALT < 5 × ULN if patients with liver metastases;

Serum total bilirubin (TBIL) ≤2×ULN;

International Normalized Ratio (INR) ≤1.5×ULN, or Activated Partial
Thromboplastin Time (APTT) ≤1.5×ULN;
8.
Females of childbearing potential must have had a pregnancy test with a negative result
within 7 days prior to initiating treatment.
9.
Male and female subjects of childbearing potential must agree to use a reliable method
of contraception for the duration of the trial and for at least 6 months after the last dose.
Exclusion Criteria:
Patients with any of the following are not eligible for enrollment in this study. Sympathetic
medication patients may be treated sympathetically on a case-by-case basis at the joint
judgment of the PI and the investigator:
1.
Known brain metastases and/or clinical suspicion of brain metastases from the tumor
(however, patients with asymptomatic brain metastases or who have been clinically
stable for more than 3 months with local therapy may be enrolled);
2.
Subjects who have had radiotherapy within 2 months of the target lesion;
3.
Subjects with other active malignancies within the previous 5 years. Subjects who have
been completely cured and do not require follow-up therapy are excluded, except for
subjects whose malignancy is within the indications;
4.
The longest diameter of the lesion used for injection is >100 mm;
5.
Subjects who have participated or are participating in a clinical trial of another drug or
medical device within the previous 4 weeks;
6.
Subjects who are preparing for or have previously received a tissue/organ transplant;
7.
Subjects with human immunodeficiency virus (HIV) infection and AID-related
opportunistic infections within 12 months, or CD4+ T-cell (CD4+) count < 350
cells/uL; Screening Hepatitis B Surface Antigen (HBsAg) and/or Hepatitis B Core
Antibody (HBcAb) positivity with HBV-DNA above the lower limit of measurability,
Screening HCV antibody Positive subjects with HCV-RNA above the lower
measurable limit; subjects with positive syphilis spirochete serology;
8.
Subjects requiring antiviral medication during the study or within 5 half-lives of
antiviral medication at the time of first dose.
9.
Subjects requiring therapeutic anticoagulant medication during the study.
10. Subjects with an uncontrolled grade ≥3 active infection of significant clinical relevance
according to CTCAE v5.0;
11. Received antitumor agents such as chemotherapy, radiotherapy, biotherapy, endocrine
therapy, immunotherapy, etc. within 4 weeks prior to the first dose; Received small
molecule targeted therapies and oral fluorouracil analogs within 2 weeks or 5 half-lives
(whichever is longer) prior to the first dose; Received herbal or proprietary Chinese
medicines with antitumor indications within 2 weeks prior to the first dose; Received
nitrosoureas or mitomycin C; palliative radiotherapy to non-target lesions permitted (≥2
weeks prior to first dose);
12. Medication-uncontrolled hypertension or pulmonary hypertension or unstable angina
pectoris; myocardial infarction or bypass or stent surgery within 6 months prior to

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dosing; history of chronic heart failure in New York Heart Association (NYHA) criteria
grade 3-4; severe arrhythmias requiring treatment (except atrial fibrillation and
paroxysmal supraventricular tachycardia, which, in the judgment of the investigator,
have no effect on the trial), including QTcF ≥450 ms in men and ≥450 ms in women.
450ms in men and ≥470ms in women (calculated using the Fridericia formula);
cerebrovascular accident (CVA) or transient ischemic attack (TIA) within 6 months
prior to enrollment;
13. Patients with active autoimmune disease or a history of autoimmune disease with
possible relapse, but patients with the following diseases were not excluded and could
be screened further

Type 1 diabetes mellitus; and

Hypothyroidism (if controllable with hormone replacement therapy alone) ;and

Controlled celiac disease ;

Skin conditions that do not require systemic treatment (e.g., vitiligo, psoriasis,
alopecia areata) ;

Any other condition that will not reoccur in the absence of an external
trigger ;and
14. Subjects requiring treatment with systemic corticosteroids (>10 mg /day prednisone or
equivalent dose) or other immunosuppressive medications within 14 days prior to the
first dose or during the study period, except as follows:

Adrenergic replacement steroids (prednisone ≤10 mg / day or equivalent dose
of a similar drug) ;.

Topical, ophthalmic, intra-articular, intranasal, or inhaled corticosteroids.

Prophylactic short-term (≤7 days) use of corticosteroids (e.g., allergy to
contrast media) or for the treatment of non-autoimmune disorders (e.g., delayed
hypersensitivity reactions caused by contact allergens);
15. Subject has a tumor located in a high-risk location (including in a mucosal area, or in
close proximity to the airway, major blood vessels, or spinal cord) that may result in
occlusion or compression due to tumor enlargement, or erosion into major blood
vessels due to necrosis, or encasement of major vascular structures (e.g., carotid
arteries), tumors adjacent to important neurovascular structures, or other tumors
deemed unsuitable for intratumoral injections;
16. Subjects will be required to receive any live vaccine during the Screening and
Treatment Periods;
17. Subject is allergic to any component of the investigational drug, immunotherapy or
related medications;
18. Subjects with concomitant mental illness, alcoholism, inability to quit smoking, drug
abuse or substance abuse;
19. Pregnant or lactating females;
20. Adverse effects of prior antineoplastic therapy that have not recovered to (CTCAE 5.0)
Grade 1 (except alopecia);
21. Serious uncontrollable disease, as determined by the investigator, or the presence of
other conditions that may interfere with the receipt of treatment under this study and are
considered unsuitable for participation in this study;
22. Other conditions deemed unsuitable for enrollment by the investigator.
Basis
for
Starting
Dose Selection
In non-clinical studies, rhesus monkeys were injected intravenously with 8.0×
109PFU/kg and 8.0×1010PFU/kg OVV-01 for 2 cycles (QD of 7 days with a 5-day cycle
interval), followed by a 4-week recovery period after a toxicology study that showed a
maximum non-severe toxicity dose (HNSTD) of 8.0×1010PFU/kg. after conversion, the
Human Equivalent Dose (HED) was 2.58×1010PFU/kg, which corresponds to a dose of 1.55
×1012PFU/subject.
In a GLP toxicology study in tumor-bearing mice, repeated intratumoral and
intravenous injections of OVV-01 for 2 cycles (1 cycle in 7 days, with 1 day off in between),
followed by a 7-day recovery period, showed a HNSTD of 3.0×109PFU/mouse
(intratumoral) + 1.2×109PFU/mouse (intravenous). Converted from 20 g of mouse body
weight, the HED was 1.22×1010PFU/kg (intratumoral) + 4.88×109PFU/kg, which

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corresponds to 7.32×1011PFU/subject (intratumoral) + 2.93×1011PFU/mg (intravenously).
In the completed dose-escalation study (RR-001), 18 patients with advanced solid
tumors received intra-tumoral injections of OVV-01 Injection in four dose groups (6×
107PFU, 6×108PFU, 7×109PFU, and 1.2×1011PFU) administered every two weeks in
multiple doses (1 to 6 doses). No serious adverse events or DLTs related to the study drug
occurred in any of the dose groups, and no MTDs were achieved.
In the ongoing dose-escalation study (RR-008), four patients received OVV-01 Injection via
intra-tumor injection at a dose of 1.2 × 1011PFU once daily for 6 consecutive days for 2
weeks. As of the cut-off date (December 16, 2024), there were no DLT events or serious
adverse events, and the treatment demonstrated a favorable safety and tolerability profile.
Taken together, these data support the proposed clinical IV starting dose of 6×
1010PFU/subject and the combined starting dose of 6 × 1010PFU/mL (intratumoral) + 6 ×
1010PFU/mL (IV) administered multiple times by once-daily dosing.
Study Intervention
VSV-02 Injection, provided by Shanghai Rongrui Pharmaceutical Technology Co.
Specification: 1mL/strike. Labeled dose: viral titer of 3.0×1010PFU/mL, administered
intravenously, intratumorally.
VSV-02 injection is administered on Day 1 (D1) of each cycle, every 3 weeks for one
treatment cycle, up to a maximum of 6 cycles, and IV and intratumoral injections are
administered on the same day. Subjects were enrolled in fixed dose groups.
Dose administered: 6 × 1010PFU/mL (it.) + 6 ×1011PFU (iv.).
If DLT occurs during the DLT observation period, VSV-02 administration will be
discontinued. If DLT does not occur, treatment will continue until disease progression, the
subject develops intolerable toxicity, the subject withdraws informed consent, the subject
dies, is lost to follow-up, the investigator determines that it is in the patient's best interest to
terminate treatment, or 6 consecutive cycles of administration have been completed,
whichever occurs earliest.
Dosing regimen
The volume of VSV-02 injected intratumorally was determined based on the size of the
tumor lesion and was given to the maximum volume possible according to the guidelines in
the table below. The investigator evaluated the size of the subject's injected lesion within 24
h prior to each injection to determine the volume of study drug to be injected. The total
injection volume of all lesions per subject per dosing day was not to exceed 10 mL.
Guidelines for Injection Volume of VSV-02 Injection Based on Tumor Size
Lesion size (longest diameter)
Injection volume
≤0.5 cm
0.5 mL
>0.5 cm and ≤1.0 cm
1.0 mL
>1.0 cm
For every 1.0 cm increase in lesion
size (rounded) from 1.0 cm, increase
the injection volume by 1.0 mL from
1.0 mL (e.g., 3.0 mL for a 3.0 cm
lesion).
Injection:
（1）
It may not be possible to inject all lesions at a time; prioritize the largest lesion and
inject other lesions according to the size of the lesion until the maximum delivery
volume is reached. The same lesion should be injected each time unless the injected
lesion shrinks to the point where it is unacceptable to inject.
（2）
If there is residual drug due to shrinkage of the tumor lesion, the new lesion may be
selected for injection.
Sample size
3-6 cases according to clinical needs
Study Suspension
Rules
SMC will require suspension of enrollment and drug administration until the situation can
be assessed when the following occurs

Death occurring within 30 days of study drug administration (unless clearly due to
disease progression)

Deaths that the investigator believes are at least potentially related to the study drug

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
Two Grade ≥4 DLTs in 2 subjects

Any grade 4 hypersensitivity reaction, immediate onset severe allergic reaction
Safety/tolerability
evaluation
Adverse events occurring throughout the study period were evaluated based on the
safety analysis set, looking at DLT and MTD according to CTCAE v5.0.Safety indicators
included: adverse events (CTCAE v5.0), laboratory tests (routine blood, blood biochemistry,
coagulation function, and urinalysis, etc.), electrocardiograms, vital signs, and physical
examination.
Efficacy Evaluation
Tumor efficacy evaluation was assessed by the investigator according to RECIST 1.1
criteria. In this study, after the first imaging progression as determined by the investigator
according to RECIST 1.1 criteria, subjects were allowed to continue treatment with VSV-02
Injection if the investigator determined that no clinical deterioration had occurred; however,
subsequent tumor evaluations should be performed again after at least 4 weeks to confirm
disease progression according to iRECIST. Clinical stability was defined as the absence of
clinically significant signs and symptoms suggestive of disease progression (including
abnormal laboratory test values), no reduction in Eastern Cooperative Oncology Group
(ECOG) physical status score, no rapid disease progression, and the absence of progressive
tumors (e.g., spinal cord compression) at important anatomical sites requiring other urgent
medical intervention. Subjects judged to be clinically unstable should terminate trial
treatment after the first imaging disease progression evaluated by the investigator and
without the need for repeat imaging to confirm disease progression.
Efficacy endpoints include ORR, DCR, DoR, PFS, and OS.
Evaluation of
biodistribution and
viral shedding
Biodistribution and viral shedding will be evaluated by detection of viral gDNA in
blood samples and shed samples (urine, feces, saliva and injection sites) using quantitative
polymerase chain reaction (qPCR) analysis. If positive viral gDNA is detected in
biodistribution and shedding samples using qPCR, the TCID50will be used to assess viral
infectivity, and it is recommended that testing be performed according to protocols, but not
mandatory if circumstances do not permit.
Immunogenicity
Evaluation
Evaluate the time, titer, and subject rate of anti-VSV-G antibody (IgG) production in
treated subjects. Evaluated only in subjects who received at least one dose of 0VV-01 and
provided a baseline sample and at least one post-treatment sample, and testing is
recommended as specified in the protocol or not mandatory if not allowed.
Biomarker and
Cytokine Evaluation
Biomarker and cytokine assays will evaluate the expression of NY-ESO-1 antigen, PD-
L1, and lymphocytes in tissue samples, and will detect levels of NY-ESO-1 antigen,
cytokines, and lymphocytes in blood samples. Specific assays may be performed
according to study needs and study realities.
Statistical Analysis
Analysis Sets
Full Analysis Set
(FAS)
Includes all subjects enrolled who have used the test drug at
least once. The FAS will be used for demographic data,
baseline descriptive analysis, medication adherence,
medication combinations during the trial, and efficacy analysis.
Efficacy Evaluable
Set (EEAS)
A subset of the FAS that includes subjects with at least one
post-treatment tumor assessment. The EEAS will be used for
efficacy analysis.
Safety Set (SS)
Includes all subjects who have received at least one dose of
the investigational drug; SS will be used for safety and
tolerability analyses.
Biodistribution
Analysis Set
This analysis set will include all enrolled subjects who have
received at least one dose of the test drug and have completed
at least one post-dose biodistribution blood collection. This
analysis set will be used to assess biodistribution.
Stool Assessable
Analysis Set
This analysis set will include enrolled subjects who have
received at least one trial drug and completed at least one fecal
swab collection. This analysis set will be used to assess the
level of VSV-02 Injection gDNA and active virus detected in
fecal samples.
Urine Assessable
This analysis set will include enrolled subjects who have

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Analysis Set
received at least one trial drug and have completed at least one
urine swab collection during the treatment period. This analysis
set will be used to assess the level of VSV-02 Injection gDNA
and active virus detected in urine swab samples during the
Treatment Period.
Saliva Assessable
Analysis Set
This analysis set will include enrolled subjects who have
received at least one trial drug and have completed at least one
saliva swab collection during the treatment period. This
analysis set will be used to assess the level of VSV-02
injectable gDNA and active virus detected in saliva swab
samples during the treatment period.
Injection Site
Assessable Analysis
Set
This analysis set will include enrolled subjects who have
received at least one trial drug and have completed at least one
injection site swab collection. This analysis set will be used to
assess the levels of VSV-02 Injection gDNA and active virus
detected on the surface of the injection site.
Pharmacodynamic
Analysis Set
This analysis set will enroll subjects who have received at
least one trial drug and have at least one assessable biomarker
or cytokine parameter. This analysis set will be used to assess
biomarker and cytokine levels of VSV-02 Injection.
Immunogenicity
Analysis Set
This analysis set will include all subjects who have received at
least one trial drug and have data from at least one post-
baseline immunogenicity sample. This analysis set will be used
to assess the immunogenicity of VSV-02 Injection.
Statistical analysis will be performed using SAS 9.4 (or newer) statistical software.
Measurement information is described statistically by the number of cases, mean, standard
deviation, median, maximum and minimum values. Count data or grade data were
statistically described by the number of cases and percentage.
Safety Evaluation
Safety evaluation will be analyzed on the safety analysis set.
Abnormalities of all examination items will be summarized in the form of pre- and
post-treatment cross-tabulation (according to the clinician's judgment) for the physical
examination, 12-lead electrocardiogram (ECG), and clinical laboratory examination indexes
in a categorical manner. Descriptive summaries of the 12-lead electrocardiogram (ECG),
laboratory tests, and vital signs, including the observed values at each time point and their
changes relative to baseline.
All adverse events were coded according to System Organ Classification (SOC) and
Preferred Terminology (PT) using the International Medical Dictionary of Terms (MedDRA)
version 22.0 or above. Categorize and summarize the coded adverse events: summarize the
number and percentage of occurrences describing all adverse events, treatment-emergent
adverse events (TEAE), serious adverse events, treatment-emergent serious adverse events,
adverse events leading to termination of treatment, and deaths associated with adverse
events; summarize all treatment-emergent adverse events and serious adverse events by SOC
and PT.
List all adverse events, including subject number, age, dose group, adverse event name,
description, start date, stop date, NCI-CTCAE 5.0 level, whether serious adverse event,
relationship to study drug, effect on study drug, regression, etc.
Efficacy Evaluation
Efficacy evaluation will be based on FAS and EEAS. ORR and DCR will be assessed
based on RECIST V1.1 and iRECIST. ORR is defined as the percentage of subjects
achieving CR or PR. DCR is defined as the percentage of subjects achieving CR, PR or SD.
95% confidence intervals (CI) for ORR and DCR were calculated using the Clopper-Pearson
method.
DoR, PFS and OS: The median survival time and its 95% CI will be estimated using
the Kaplan- Meier method, and the survival rate and 95% CI will be estimated for each time
point.The standard error of the Kaplan-Meier curve estimates will be calculated using the
Greenwood formula. Kaplan- Meier curves will also be plotted.

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Evaluation of biodistribution and viral shedding
The proportion of subjects meeting the criteria for detectable gDNA at each time point
will be calculated. Statistics will be presented by dose level. Compassionate medication
patients will not be mandatorily invited for testing if circumstances do not permit.
Immunogenicity Evaluation
Descriptive statistical analysis of changes in the production of anti-VSV-G antibodies
(IgG) in subjects at each time point after treatment. Compassionate medication patients
were not compulsorily invited for testing if circumstances did not permit.
Evaluation of biomarkers and cytokines
Biomarkers and cytokines and their changes relative to baseline were statistically
characterized according to their profile. Exploratory analyses of pharmacodynamic
parameters were performed as needed. Compassionate medication patients are not
mandatorily invited for testing if circumstances do not permit.
Duration of the test:
The study will consist of the following phases: a screening period (28 days prior to
dosing), a treatment period (administration of VSV-02 injection until disease progression,
intolerable toxicity in the subject, withdrawal of informed consent by the subject, death of
the subject, loss to follow-up, termination of treatment as deemed by the investigator to be in
the best interest of the patient, or multiple administrations of VSV-02 have completed 6
cycles, whichever occurs earliest.) and follow-up periods (safety follow-up (28 days after the
last dose) and survival follow-up (every 12 weeks until the subject withdraws informed
consent, dies, is lost to follow-up, receives another antitumor therapy other than that
specified in the protocol, or the study is completed, whichever occurs earliest).) .

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1
INTRODUCTION
1.1 BACKGROUND
1.1.1
Disease background
In 2022, there will be an estimated 20 million new cancer cases and 9.7 million deaths. The
number of people surviving within 5 years of a cancer diagnosis is estimated to be 53.5 million. About
one in five people develop cancer in their lifetime, and about one in nine men and one in twelve
women die from cancer.In 2022, lung cancer was the most common cancer worldwide, accounting for
12.4% of all new cases; female breast cancer ranked second (2.3 million cases, 11.6%), followed by
colorectal cancer (1.9 million, 9.6%), prostate cancer (1.5 million. 7.3%) and stomach cancer (970,000
cases, 4.9%). Lung cancer is also the leading cause of cancer deaths (1.8 million deaths, 18.7% of all
cancer deaths), followed by colorectal cancer (900,000 deaths, 9.3%), liver cancer (760,000 deaths,
7.8%), breast cancer (670,000 deaths, 6.9%) and stomach cancer (660,000 deaths, 6.8%). Malignant
tumors (cancer) have become one of the major public health problems that seriously threaten the
health of the population[1] .
Although cancer treatment has made great progress in multidisciplinary integrated therapy such
as surgery, chemotherapy, radiotherapy and molecular targeted therapy, recurrence and metastasis of
tumors still lack effective treatment so far. The direction of tumor treatment has shifted from
traditional treatments (e.g., surgery, chemotherapy, radiotherapy) to more targeted and personalized
interventions. Among these, the emergence of immunotherapy has brought about significant changes
in the field of cancer treatment. Immune checkpoint inhibitors, such as antibodies to programmed cell
death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1), activate the body's immune
system, allowing it to recognize and attack cancer cells[2] . Considering the heterogeneity of solid
tumors, the use of combination therapies is essential to improve treatment outcomes. Researchers have
attempted to improve treatment efficacy and break through resistance mechanisms by combining many
different treatments, such as chemotherapy, targeted therapy and immunotherapy[3] . Despite the
favorable results of anti-PD-1/PD-L1 antibody therapy, most patients are not sensitive to the treatment
and some sensitive patients do not achieve complete remission after treatment[4][5] . Anti-PD-1/PD-
L1 antibody therapy has the strongest antitumor effect in tumors with high levels of tumor-infiltrating
lymphocytes, high mutational burden, and increased PD-L1 expression[6] . These responsive tumors
are referred to as immunologically "hot tumors" as opposed to "cold tumors" that lack response.
Oncolytic viruses (OVs) represent an ideal therapeutic pathway for enhancing the response of patients
and certain tumor types to anti-PD-1/PD-L1 antibody therapy.
The emergence of oncolytic virus (OV) therapy has provided a promising new therapeutic

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approach in the field of cancer treatment, offering a new strategy for the treatment of a wide range of
solid tumors. Oncolytic viral therapy employs specific types of viruses to give full play to their
selective infection and lysis of cancer cells without harming normal healthy cells. By using the
replication ability of viruses in host cells, lysing the cells and releasing the progeny viruses, the
progeny viruses re-infect and lyses the new tumor cells, and finally destroys the tumor foci. . Currently,
five lysogenic virus products have been approved and marketed worldwide: Rigvir (ECHO-7 virus),
Ancoris (recombinant human adenovirus type 5), Imazalil (human adenovirus type 5), T-Vec (HSV)
and Delytact (HSV). With the deepening of medical research, the application of oncolytic viruses in
the field of anti-tumor therapy is increasing, bringing more hope to patients with malignant tumors.
Several preclinical and clinical studies have demonstrated the significant therapeutic potential of
lysosomal viruses in solid tumors.A study conducted by Kaufman et al. in subjects with advanced
melanoma confirmed the efficacy of the lysosomal viral drug, T-VEC.T-VEC not only directly
destroys tumor cells, but also has an immune-stimulating effect that activates the anti-tumor immune
response[8] . Lysoviral therapy can also be combined with other therapeutic approaches to achieve
better results. Studies have shown that the combination of T-VEC and PD-1 antibodies can enhance
tumor regression and achieve durable remission, confirming the potential of such combinations to
improve treatment outcomes[9] . The selective tumor killing and immunostimulatory effects of
lysosomal viral therapies offer a new avenue for more effective and targeted cancer treatment
strategies.
1.1.2
Investigational Drugs and Therapeutic Context
Oncolytic viral products offer many advantages and are therefore a promising area of research in
the field of cancer therapy. Derived from natural or genetically modified or modified classes of viruses,
lysoviruses are versatile and novel therapeutic agents. Common oncolytic viruses include mutant
adenovirus ONYX-015 (dl1520), HSV-1 mutant G207, human retrovirus 3, vesicular stomatitis virus
(VSV) and EBV. It is also known as conditional replication virus or selective replication virus, which
can selectively infect tumor cells and replicate in them, and eventually lyses and kills the tumor cells
and releases daughter virus particles to further infect the surrounding tumor cells, while there is no
replication or killing effect in the cells of normal tissues, and it can also induce specific anti-tumor
immune response and so on.
In order to obtain lysogenic adenoviruses with good tumor-targeting properties, many
modification strategies have been developed in the past decades. As early as 2003 Giedlin MA
proposed that Vesicular stomatitis virus (VSV) could be used as an oncolytic virus for tumor treatment.
The rationale is that it cannot interact with endogenous IFN-β in normal cells, but can only selectively
amplify and grow in tumor cells[10] . In 2009, McMaster University, Canada, demonstrated that VSV

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can be used as a new tumor drug carrier to promote immune response[11] . In recent years, researchers
have paid more attention to the study of VSV, a non-pathogenic, enveloped negative-stranded RNA
elastovirus that mainly infects rodents, cattle, swine, and horses, with a very low prevalence in the
population, and only a few cases of infection in animal breeders and laboratory personnel with mild or
no symptoms after infection. VSV is characterized by rapid replication and trans-synaptic speed, and
ultra-high gene expression. Compared to other tumor lysing cytovirus platforms currently under
development, VSV has a small genome and is easy to manipulate; has a shorter replication time; has
an independent cell cycle; can grow rapidly in a wide range of cell lines with high titers, allowing for
large-scale production; and has no translational risk of cytoplasmic replication of the host cell. This
lysosomal cytotoxic virus does not integrate into DNA and has been modified to avoid the neurologic
inflammation caused by wild-type viruses.
In recent years, with the continuous development of the VSV lysovirus platform, many
recombinant variants of lysoviruses based on VSV modification have emerged, which are mainly
aimed at improving tumor targeting, prolonging in vivo retention time, and enhancing the effect of
lysis of tumors, etc., which have enhanced the safety and efficacy of VSV lysoviruses for tumor
therapy, and a series of VSV-based lysoviral agents have gradually entered the stage of clinical trials.
VSV-IFNβ has entered phase I clinical trials for the treatment of patients with advanced or relapsed
refractory melanoma, hepatocellular carcinoma, endometrial carcinoma, leukemia, lymphoma, etc.
(NCT03865212, NCT01628640, NCT03017820 and NCT03120624). Combination regimens of
VSV+CTLA-4 antibody, TIM3 antibody or LAG3 antibody are also being evaluated. VSV-IFNβ-NIS
(thyroid sodium iodide homotransporter protein) in combination with a PD-1/PD-L1 antibody such as
Pembrolizumab/Avelumab is currently undergoing a Phase I clinical trial in the treatment of patients
with relapsed, refractory solid tumors, including non-small-cell lung cancer and squamous carcinoma
of the head and neck (NCT02923466 and NCT03647163). On July 20, 2020, Vyriad announced the
completion of enrollment of the first subject in a clinical Phase II trial of its lysosomal virus product,
Voyager-V1. The study is an open study of Voyager-V1 in combination with a PD-1 inhibitor
(Cemiplimab) for the treatment of subjects with four relapsed refractory progressive tumors, with 152
subjects planned to be enrolled. The study covers four tumor types, including non-small cell lung
cancer and melanoma that have progressed after the application of checkpoint inhibitors, as well as
hepatocellular carcinoma and endometrial cancer (NCT04291105).VSV has been successful in the
field of lysosomal viruses, and has a very promising application.
CD3/PD-L1 bispecific antibody is an emerging and highly promising strategy for tumor
immunotherapy. It combines two different immunotherapeutic mechanisms in one, aiming to activate
the immune system more effectively and overcome the immune evasion mechanism of tumors. Its core

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mechanism of action and advantages are described below:
Core mechanism of action
1. Simultaneous targeting of two key molecules:

CD3: A key signaling molecule located on the surface of T cells and part of the T cell
receptor complex. Binding to CD3 activates T cells, whether or not their TCR recognizes
tumor antigens.

PD-L1: Programmed death ligand-1, usually highly expressed on a variety of tumor cells
and other cells in the tumor microenvironment (e.g., myeloid cells.) Binding of PD-L1 to
PD-1 on T-cells transmits inhibitory signals that lead to depletion, inactivation, or
apoptosis of T-cells, and is an important mechanism of immune escape from tumors.
2. "Bridging" effect:

One arm (Fab) of the bispecific antibody binds PD-L1 on tumor cells or cells in the tumor
microenvironment.

The other arm binds CD3 on T cells.

In this way, the bispecific antibody acts as a "bridge", physically pulling and anchoring the
T-cells next to the PD-L1-expressing tumor cells.
3. Dual action:

Forced T-cell activation: By binding to CD3, a strong activation signal is delivered directly
to the T-cells. These T cells can be reactivated even if they have low affinity for tumor
antigens or are in a resting/depleted state.

Blocking Immune Checkpoints: By binding to PD-L1, the interaction of PD-L1 with PD-1
on T cells is blocked. This removes the "brakes" (inhibitory signals) that the tumor applies
to the T-cells, unsuppressing T-cell function.

Synergistic effect: Based on the physical connection, the simultaneous provision of T-cell
activating signals (CD3) and removal of inhibitory signals (PD-L1 blockade) creates a
powerful, localized immune-activating effect within the tumor microenvironment. This
significantly enhances the ability of T cells to recognize and kill tumor cells.
Role and advantages for the treatment of tumors
1. Overcome immunosuppression in the tumor microenvironment: Directly target PD-L1, a key
immunosuppressive factor in the tumor microenvironment, while activating T cells to
effectively counteract the tumor's immune escape strategy.
2. Recruitment and activation of bystander T-cells: It does not require T-cells to be specifically
activated by tumor antigens or to recognize tumor antigens beforehand (traditional TCR-
dependent approach). It is able to recruit any T cells in the tumor microenvironment or in

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circulation ("bystander T cells"), regardless of their TCR specificity, forcing them to
recognize and attack nearby PD-L1-positive tumor cells. This addresses the lack of sufficient
tumor-specific T cell infiltration within the tumor.
3. Enhanced T-cell killing potency: Dual action (activation + disinhibition) puts recruited T-cells
in a highly activated state, significantly enhancing their cytotoxicity against tumor cells.
4. Potentially Overcome PD-1/PD-L1 Inhibitor Resistance: For patients who are ineffective or
resistant to PD-1/PD-L1 inhibitors alone, CD3/PD-L1 dual antibody provides a different
mechanism. It not only blocks the PD-1/PD-L1 pathway, but also actively pulls T-cells to the
tumor and forces activation, which may be effective in some resistant patients.
5. Targets tumor locally, potentially reducing systemic toxicity: Theoretically, its activity relies
on binding to both PD-L1-expressing tumor cells and T-cells, so that activation of T-cells and
cytokine release occurs primarily at the tumor site (although systemic toxicity remains a
concern), and is likely to be more controllable than toxicity of systemic T-cell activating
drugs (e.g., anti-CD3 monoclonal antibodies).
6. Applicable to PD-L1-positive tumors: Provides a new therapeutic option for a wide range of
solid tumors with positive PD-L1 expression.
Challenges and Potential Risks
1. Cytokine Release Syndrome: This is the primary safety concern. Strong activation of T cells
may lead to rapid release of large amounts of inflammatory cytokines (e.g., IL-6, IFN-γ,
TNF-α, etc.) into the bloodstream within a short period of time, resulting in systemic
inflammatory reactions such as fever, hypotension, and respiratory distress, which may be
life-threatening in severe cases. Close monitoring and management strategies (e.g., stepwise
dosing, prophylactic dosing) are required.
2. Neurotoxicity: Some patients may experience neurologic side effects such as headache, tremor,
confusion and even seizures, the mechanism of which is not fully understood.
3. "Target-dependent" off-target toxicity: T cells may be recruited and attack cells that express
low levels of PD-L1 in normal tissues, causing tissue damage (e.g., hepatotoxicity,
pneumonia, etc.).
4. T-cell depletion: Continued strong stimulation may lead to eventual depletion of activated T-
cells, affecting long-term efficacy.
5. Complex production process: Bispecific antibodies are more complex than monoclonal
antibodies, making production and quality control more challenging.
Summary
CD3/PD-L1 bispecific antibody is an innovative immunotherapeutic weapon. It generates a

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powerful anti-tumor immune response locally by physically connecting T-cells to PD-L1-positive
tumor
cells,
simultaneously
forcibly
activating
T-cells
and
lifting
PD-1/PD-L1-mediated
immunosuppression. Its core advantage lies in its ability to actively recruit and activate "bystander" T
cells to overcome the inhibition of the tumor microenvironment, and is expected to resolve the
problem of resistance to some PD-1/PD-L1 inhibitors. However, its strong immune activation ability
also brings significant risk of side effects, especially CRS, which is a key challenge to be managed and
overcome in clinical applications. Several CD3/PD-L1 dual antibodies are currently in clinical trials
(e.g., phase I/II) and have shown preliminary anti-tumor activity in a variety of solid tumors (e.g., non-
small cell lung cancer, head and neck squamous carcinoma, gastric cancer, ovarian cancer, etc.);
however, their long-term efficacy and safety still need to be validated in larger clinical trials.
1.1.3
Overview of preclinical studies
Information on preclinical studies is detailed in the Investigator's Manual.
1.1.3.1 Pharmacodynamic Studies
1.1.3.1.1
In Vitro Pharmacodynamics
VSV-M3-BITE P5 synergizes tumor killing by PBMC cells
To verify whether BITE activates PBMC cells to synergize VSV virus for tumor killing, 2 E4
cells were spread into 96-well culture plates for group experiments using .A549 cell digestion and
counting.
Viral infection for 24.5h
A549+PBMC+VSV-M3-BITE group elevated tumor killing by 51.81% relative to A549+VSV-M3-
BITE
The A549+PBMC+VSV-M3-EGFP group showed a 31.7% increase in tumor killing relative to the
A549+VSV-M3-EGFP group.
This result proves that any VSV virus can activate PBMC cells to achieve synergistic tumor killing
effect
A549+PBMC+VSV-M3-BITE group showed a 13.13% increase in tumor killing compared to
A549+PBMC+VSV-M3-EGFP group.
This result demonstrates that VSV-M3-BITE can specifically activate PBMC cells, thus enhancing
the tumor killing effect.
Viral infection for 28 h
A549+PBMC+VSV-M3-BITE group increased tumor killing by 31.72% compared to A549+VSV-
M3-BITE group.

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The A549+PBMC+VSV-M3-EGFP group showed a 13.68% increase in tumor killing relative to the
A549+VSV-M3-EGFP group.
This result proves that any VSV virus can activate PBMC cells to achieve synergistic tumor killing
effect
A549+PBMC+VSV-M3-BITE group showed a 15.81% increase in tumor killing compared to
A549+PBMC+VSV-M3-EGFP group.
This result demonstrates that VSV-M3-BITE can specifically activate PBMC cells, thus enhancing
tumor killing.
Conclusion: Any VSV virus can activate PBMC cells to synergistically kill A549 tumor cells,
and VSV-M3-BITE can specifically activate PBMC cells on this basis to increase the tumor killing
effect by about 15%.
1.1.3.1.2
In vivo pharmacodynamics and toxicology
Pharmacodynamic experiments of lysovirus VSV-02 in subcutaneous transplantation tumor
model of LLC mouse lung cancer cell line C57BL/6 mice
In this study, the antitumor activity of the test substance VSV-02 blistering stomatitis virus
injection (hereinafter referred to as VSV-02) was evaluated in vivo in animals using an animal model
of subcutaneous transplantation tumor in LLC mouse lung cancer cell line C57BL/6 mice.
Method: Approximately 5×10⁶ cells/mL of LLC cells (with consecutive passage generations less
than 10) were suspended in PBS and subcutaneously inoculated into the right dorsal region of mice at
a volume of 100 μL per mouse. On day 8 after LLC cell inoculation, the mice were randomly divided
into 4 groups based on body weight and tumor volume:
G1: Vehicle control group, i.t., QOD × 7 times;
G2: VSV-02 3×10⁸ PFU/mouse, i.t., QOD × 7 times;
G3: VSV-02 3×10⁸ PFU/mouse, i.v., QOD × 7 times;
G4: VSV-02 3×10⁸ + 3×10⁸ PFU/mouse, i.t. + i.v., QOD × 7 times.
Each group consisted of 6 animals. The day of grouping and administration was defined as Day 0.
During the administration period, tumor volume was measured and recorded twice per week. Body
weight was measured and recorded twice per week before the first administration and during the
administration period. Body weight was also recorded when animals became moribund and were
euthanized. At the experimental endpoint, all mice were euthanized.

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RESULTS: In this experiment, compared with the G1 Vehicle control group during the same
period, the tumor volume of the G2 VSV-02 3×108PFU/only intratumorally administered group was
significantly lower than that of the control group at Day 17, with a TGI% of 85.67%, and that of the
G3 VSV-02 3×108PFU/only intravenously administered group was significantly lower than that of the
control group, with a TGI% of 50.15 %. TGI% was 50.15%; G4 VSV-02 3×108+3×108PFU/only
Intratumoral + intravenous administration group had a significantly lower tumor volume than that of
the control group, with a TGI% of 92.50%.
The TGI% was 92.50% in the control group. G2: VSV-02 3×108PFU/only, i.t., QOD×7times; G3:
VSV-02 3×108PFU/only, i.v., QOD×7times; G4: VSV-02 3×108+3×108PFU/only, i.t. + i.v.,
QOD×7times; G4: VSV-02 3×108+3×108PFU/only, i.t. + i.v., QOD×7times. 7times None of the
average body weights of the animals on Day 17 were significantly reduced compared to Day 0.
Overall the mice were tolerant to the test drug VSV-02.
Effect of Subject VSV-02 on Body Weight of Animals in the Lung Cancer Homograft
Tumor Model in LLC Mice
During the experimental period, the overall body weight of the mice in each group continued to
increase and their mental status was good. The lysate control group, G2 VSV-02 3×108PFU/unit, i.t.,
QOD×7times administration group, G3 VSV-02 3×108PFU/unit, i.v., QOD×7times administration
group, and G4 VSV-02 3×108+3×108PFU/unit, i.t. + i.v., QOD×7times administration group. 7times
dosing groups Day 17 mean body weight of animals were not significantly toxic compared to Day0.
Effect of Subject VSV-02 on Body Weight of Hormonal Animals in the Lung Cancer
Homograft Tumor Model in LLC Mice
Grou
p
Numbe
r of
animals
N
Dosing regimen
Mean body weight of
animals
(g, MeanSEM)
Mean %
change in
body
weight
Day17vs
Day0
Numbe
r of
drug-
related
animal
deaths
Day 0
Day 17
1
6
Vehicle,i.t., QD×7times
19.5±0.28
24.16±0.28
24.34% (+
4.66g)
0/6
2
6
VSV-
02,3×108PFU/only,
i.t.,QOD×7times
20.02±0.16
20.72±0.31
3.49%
0.70g)
0/6
3
6
VSV-02, 3 ×
108PFU/only, i.v., QOD
× 7times
19.91±0.28
20.86±0.87
6.41 %
(0.96g)
0/6

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4
6
VSV-
02,3×108+3×108PFU/onl
y,i.t.+i.v., QOD×7times
19.49±0.16
20.37±0.47
4.43%
(0.88g)
0/6
The effect of subject VSV-02 on the body weight of LLC murine lung cancer homograft
tumor model animals
CONCLUSION: Under the conditions of this experiment, the growth of LLC cell lines was
normal and the tumor growth curves conformed to the pattern of historical data. Compared with the
control group G1 Vehicle, i.t., QOD×7 times, the G2 VSV-02 3×108PFU/only, i.t., QOD×7 times
group,
the
G3
VSV-02
3×108
PFU/only,
i.v.,
QOD×7
times
group,
the
G4
VSV-02
3×108+3×108PFU/only, i.t. + i.v., QOD×7 times group all demonstrated a significant inhibitory effect
on tumor growth (p<0.05), with TGI% of 85.67%, 50.15% and 92.5% at Day 17, respectively. Among
them, 3/6 tumors disappeared in the G4 intratumoral + intravenous group on Day 17, which showed
the most obvious tumor suppression effect.
The lysate control group, G2 VSV-02 3×108PFU/only, i.t., QOD×7times administration group,
G3
VSV-02
3×107PFU/only,
i.v.,
QOD×7times
administration
group
and
G4
VSV-02
3×108+3×108PFU/only, i.t. + i.v., QOD× There was no significant toxic response in any of the 7times
dosing groups up to Day 17 mean animal body weight compared to Day0 (p > 0.05).

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Lysovirus VSV-CD3-PDL1 Efficacy Experiment in MC38 Mouse Colon Cancer Cell Line
C57BL/6J Mouse Subcutaneous Transplant Tumor Model
In this study, we evaluated the antitumor activity of the subject VSV-CD3-PDL1 blistering stomatitis
virus injection (hereinafter referred to as VSV-CD3-PDL1) using the mouse colon cancer MC38
syngeneic transplantation tumor model and compared the effects of different doses on the antitumor
effects of the subject VSV-CD3-PDL1.
METHODS: About 2 × 106 cells /mL MC38 cells (consecutive culture generations less than 10
generations) were suspended in PBS and inoculated into the right dorsal subcutaneous area of mice by
subcutaneous injection, with an inoculation volume of 100 μL/only. Mice were randomly divided into
2 groups according to body weight and tumor volume, G1: Vehicle control group, i.t., Q2D×7times;
and G2 VSV-CD3-PDL1 3×108 pfu/one, i.t., Q2D×7times administration group with 6 animals in
each group. The day of group administration was defined as Day 0.
Effect of subject VSV-CD3-PDL1 on body weight of MC38 mouse colon cancer homograft
tumor model animals
During the experimental period, the mice in each group showed a continuous increase in body
weight and good mental status. The average body weight of animals in the lysate control group, G2
VSV-CD3-PDL1 3×108pfu/only, i.t., Q2D×7times administration group on Day13 did not show any
significant toxicity response compared with that on Day0.
Effect of Subject VSV-CD3-PDL1 Administered Alone on Body Weight of Hormonal Animals
in MC38 Mouse Colon Cancer Homograft Tumor Model
Group
Number
of
animals
N
Dosing regimen
Mean body weight of
animals
Mean body
weight % change
Day 13vs Day 0
Number of
drug-related
animal
deaths
(g, Mean
SEM)
Day 0
Day 13
1
6
Vehicle, i.t.,
Q2D×7
18.48±0.23
20.89±0.65
0.13% (+ 2.41g)
0/6
2
6
VSV-CD3-PDL1.
3 × 108pfu/only,
i.t., Q2D × 7
18.78±0.14
20.53±0.25
0.09 % (+1.75g)
0/6

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Effect of subject VSV-CD3-PDL1 on body weight of MC38 mouse colon cancer homograft
tumor model animals
RESULTS: In this experiment, Day13, G2 VSV-CD3-PDL1 3×108pfu/only, i.t., Q2D×7times
administration group %T/CRTV was 52.67; the group of the test substance G2 VSV-CD3-PDL1 had
better inhibition of the tumor growth of the mouse colon cancer MC38.
During the experimental period, the weight of mice in each group continued to increase and their
mental status was good. There was no significant toxicity reaction in both the lysate control group and
the G2 VSV-CD3-PDL1 3×108pfu/only, i.t., Q2D×7times administration group of the average body
weight of animals on Day13 compared with that on Day0.
1.1.3.2 Pharmacokinetic study
1.1.3.2.1
Distribution.
Consistent with OVV-01, which has received FDA Clinical I and II study approval.
Repeated Dose Biodistribution Assay in C57BL/6J Hormonal Mice (Study Nos. ALFT008M and
ALFT013M, GLP)
Repeated dosing toxicity in 2 GLP loaded mice, there were differences in the dosing intervals
between the 2 experiments, but the results of the biodistribution of the 2 experiments were consistent.
The results of the biodistribution conducted along with the repeated dosing toxicity test in tumor-

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bearing mice showed that, for vector VSV, viral copy number could be detected in the blood samples
of the animals in each dosing group mainly during the dosing period, but not at the end of the recovery
period; basically, viral copy number could be detected in the tissues of the animals in each dosing
group mainly in tumors and spleens after dosing, and also at the end of the recovery period, with a
decreasing trend with the extension of time. At the end of the recovery period, viral copy number
could also be detected, and the copy number basically showed a decreasing trend with the
prolongation of time. For the tumor antigen NY-ESO-1, only tumor tissues were positive after
administration of the drug to animals in each dosing group, and the incidence or intensity of staining
was basically positively correlated with the dose, and the intensity of staining tended to decrease from
strong to weak with the prolongation of time, while no significant positivity was observed in other
organs.
Repeated intravenous administration of rhesus monkeys for 2 cycles (once a day for 7 days and
5 days off), 4 weeks off recovery toxicity test accompanied by viral shedding, and biodistribution
evaluation (Study No. AX2401P, GLP)
The results of biodistribution evaluation showed that after receiving repeated intravenous
administration of OVV-01, OVV-01 was visible in whole blood and most tissues, mainly in the spleen,
followed by the lungs: Day 20 after administration of OVV-01 in the high and low dose groups, OVV-
01 virus was detected in all tissues, except for adrenal glands and thymus, which were lower than the
lower limit of quantification in the low dose group; Day 48 after administration of OVV-01 in the high
and low dose groups. OVV-01 virus was detected in the heart, liver, spleen, and lungs in the low-dose
group and in the heart, spleen, lungs, kidneys, thymus, and sciatic nerves in the high-dose group, and
was predominantly found in the spleen, all of which showed a significant decrease from Day 20.
The results of viral shedding evaluation showed that after receiving repeated intravenous
administration of OVV-01, OVV-01 virus was detected in saliva, nasal mucus and fecal samples of the
high and low dose groups, and only in urine samples of the high dose group; at the end of the recovery
period (Day 46/47), virus was detected in only one saliva sample and one nasal mucus sample of the
high dose group, and in the rest of the dose groups each of the Virus was not detected in any of the
virus shedding samples in the remaining dose groups.
1.1.3.2.2
Metabolism
Consistent with OVV-01, which has received FDA approval for clinical studies I and II.
1.1.3.2.3
Excretion
Consistent with OVV-01, OVV-01 has received FDA Clinical I and II study approval.

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1.1.4
Overview of Clinical Studies
OVV-01 Injection has completed 1 investigator-initiated study (IIT) (RR-001) in patients with
advanced solid tumors in which subjects received a single dose and 2-weekly sequential doses for a
total of 6 doses.
In RR-001, a total of 18 subjects received study drug in 4 dose groups (6×107PFU/person: 4; 6×
108PFU/person: 4; 6 × 109PFU/person: 7; 1.2 × 10(1) (1)PFU/person: 3).3 weeks after the initial
administration of the OVV-01 injection, a 2-weekly serial dosing was initiated administration, with 6
overall administrations.
The results of this study showed that the study drug did not cause any DLT events during single
and multiple dosing in a total of 18 subjects in the low dose group of 3×107PFU/person (4 cases), the
medium dose group of 3×108PFU/person (4 cases), the high dose group of 3×109PFU/person (7
cases), and the even higher dose group of 6×1010PFU/person (3 cases), and did not serious adverse
events related to the study drug occurred, and the maximum tolerated dose (MTD) was not reached.
The overall safety profile was favorable, with no unanticipated new safety issues identified.
The most common (incidence ≥20.0%) TEAEs associated with OVV-01 Injection were fever
(12 cases, 66.7%), decreased lymphocyte count (5 cases, 27.8%), and anemia (4 cases, 22.2%).
Subjects received administration of the study drug all subjects were immunogenic positive. Live virus
particles were detected in the peripheral blood (serum) of only some of the subjects at the 0.25h, 1h,
3h, 12h, and 24h time points after subjects received study drug administration, and were not detected
in saliva, urine, or feces. No live virus particles were detected in whole blood (plasma) after subjects
received study drug administration.
Based on compliance with the protocol set, the objective remission rate (ORR16w) assessed at 16
weeks after the first treatment was 27.3%, ORR8wwas 0, ORR24wwas 27.3%, DCR24wwas 63.6%,
PFSR24wwas 43.08%, the median DoR24wwas NA, and the median overall survival was NA; in
advanced sarcoma ORR16wwas 50.0% and DCR16wwas 83.3% in subjects with advanced sarcoma, and
ORR16wwas 75.0% and DCR16wwas 75.0% in subjects with advanced soft-tissue sarcoma.OVV-01
Injection demonstrated efficacy in addition to preliminary efficacy in an advanced solid tumor
population.
1.2 Risk/Benefit Assessment
VSV-02 is an attenuated VSV virus carrying CD3/PD-L1 bispecific antibodies that selectively
infects tumors and displays potent tumor lysis efficacy against tumors.VSV-02, due to its lysogenic
viral properties, specifically replicates and expresses insertion of bispecific antibodies in tumor cells,

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which elicits spontaneous humoral and cellular immune responses, and, coupled with its restricted
expression pattern , is a good candidate target for cancer immunotherapy.
Currently, there are no similar products (VSV-vectored lyssaviruses) on the market in China or
abroad. A single intravenous dose-escalation study of VSV-IFNβ -NIS in clinical development was
conducted in patients with relapsed/refractory hematologic malignancies (NCT03017820).Fifteen
patients received VSV-IFNβ -NIS administration, and none of the four dosage groups (0.05, 0.17 , 0.5,
and 1.7 × 1011TCID50) had DLT occurred, the most common AEs observed were hematologic and
usually returned to baseline levels within 2 to 10 days, and most patients had a transient febrile
response to the viral infusion that began a few hours after the infusion and subsided overnight and was
usually associated with nausea, vomiting, hypotension, and/or mild hypoxemia. Transient elevations
of several cytokines were observed 4h after lysosomal virus infusion and returned to baseline levels at
24 or 48 hours. Various concentrations of viral particles were detected immediately, 2h, 4h, 24h, 48h,
and 72h post-infusion, but no viral persistence was observed. Anti-VSV neutralizing antibodies were
detected at 29 days post-infusion. T cells, NK cells, myeloid-derived suppressor cells (MDSC), and
myeloid cells in the peripheral blood were measured at baseline, day 3, day 8, day 15, and day 29 post-
injection, and a trend toward increased PD-1 expression on the surface of CD8+ T cells was
observed[12] . The overall safety profile of OVV-01 injection in the RR-001 study that has been
conducted with this product was favorable, with no DLT events and a total of 2 SAEs, both unrelated
to the study drug. The most common adverse reactions were fever, decreased lymphocyte count and
anemia.
In terms of efficacy, published clinical trial results for a foreign marketed lysosomal virus
product (T-Vec) are very encouraging. Other VSV-based oncolytic viral products have also been
studied in a variety of solid tumor indications. 3 of 7 patients with T-cell lymphoma (TCL)
demonstrated remission in a study of VSV-IFNβ -NIS in patients with relapsed/refractory hematologic
malignancies (NCT03017820). In the completed RR-001 study with this product, with an ORR16wof
27.3%, ORR8wof 0, ORR24wof 27.3%, DCR24wof 63.6%, and PFSR24wof 43.08%, OVV-01 Injection
demonstrated efficacy beyond preliminary efficacy in an advanced solid tumor population.
Based on results from non-clinical studies, results from approved and in-development lysosomal
viral products, and results from the clinical RR-001 study, OVV-01 has the potential to improve
therapeutic outcomes in subjects with advanced solid tumors, and the overall safety profile of OVV-01
is manageable. Taken together, the data suggest that OVV-01 is expected to be an effective
interventional therapy that provides clear clinical benefit to subjects with advanced solid tumors, while
maintaining manageable safety risks.

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2
Trial Objectives and Endpoints
Study Objectives
Study Endpoints
Primary Endpoint
Primary Endpoint

To evaluate the preliminary efficacy of
intravenous and intratumoral administration of
VSV-02 Injection in subjects with advanced solid
tumors;

Objective Remission Rate (ORR), Disease Control
Rate (DCR), Duration of Response (DoR),
Progression Free Survival (PFS) and Overall Survival
(OS);
Secondary endpoints
Secondary Endpoints

To evaluate the safety of VSV-02 Injection
administered intravenously and intratumorally in
subjects with advanced solid tumors.

Incidence and characterization of adverse events
(AE);

Changes in safety indicators such as laboratory
findings, physical examination, electrocardiogram
and vital signs compared to baseline;
3
Experimental design
3.1 Overall design.
This is an open-label, single-arm, dose-escalation Phase I clinical study designed to evaluate the
preliminary efficacy and safety of VSV-02 Injection intravenously and intratumorally in subjects with
advanced solid tumors for compassionate use in patients lacking effective treatment modalities.
Screening-eligible subjects must be subjects with histologically or cytologically confirmed
advanced malignant solid tumors and must have measurable and injectable tumor lesions, including
superficial lesions as well as deep lesions that are amenable to injection under ultrasound/CT guidance.
The study consists of a screening period, a treatment period, and a follow-up period. The
screening period lasted from the day the subject signed the ICF (Day -28) to the day before the first
dose (Day -1). Screening-eligible subjects will receive IV therapy (Part 1) or IV + intratumor therapy
(Part 2) from administered on Days 1 and 3 (D1, D3) of each cycle, with one treatment cycle every 3
weeks for a maximum of 6 cycles, with IV and intratumor administered on the same day. If DLT
occurs during the DLT observation period, VSV-02 administration will be discontinued. If DLT does
not occur, treatment will continue until disease progression, the subject develops intolerable toxicity,
the subject withdraws informed consent, the subject dies, is lost to visitation, the investigator
determines that it is in the patient's best interest to terminate treatment, or 6 consecutive cycles of
administration have been completed, whichever occurs earliest.
Some subjects may experience transient tumor growth and pseudo-progression during the first
few months after initiation of immunotherapy, followed by disease remission. After the first disease
progression in a subject, as determined by the investigator according to RECIST 1.1 criteria, subjects
will be allowed to continue treatment with VSV-02 if the investigator determines that the subject is in

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a clinically stable state and it is believed that continued treatment of the subject may be of clinical
benefit. If the imaging assessment shows disease progression as determined according to RECIST 1.1
and there is no clinical deterioration, the tumor should be evaluated again at least 6 weeks later to
confirm disease progression according to iRECIST for Cancer Immunotherapy Trials. Clinical
stability is defined as the absence of clinically significant signs and symptoms suggestive of disease
progression (including abnormal laboratory test values), no reduction in ECOG Physical Status Score,
no rapid disease progression, and the absence of progressive tumors (e.g., spinal cord compression) at
important anatomical sites that would require other urgent medical intervention. Subjects judged to be
clinically unstable should be terminated from trial treatment since the first imaging disease
progression evaluated by the investigator, and repeat imaging is not required to confirm disease
progression.
The follow-up period consisted of safety follow-up and survival follow-up, with subjects required
to return to the study center for safety follow-up within 28 days (±7 days) of the last dose if treatment
was discontinued for any reason. Subjects then enter a survival follow-up period with survival follow-
up assessments every 12 weeks until the subject withdraws informed consent, dies, loses the visit,
receives other antitumor therapy other than that specified in the protocol, or the study is completed,
whichever occurs earliest. After subjects have completed 12 cycles of multiple dosing, if the
investigator judges that subjects may still benefit from continued treatment with VSV-02 Injection,
each patient should be consulted, and if the subject requests to continue treatment, he or she may apply
for continued treatment, but must sign a separate informed consent form, the specific content of which
should be based on the actual condition of the patient, and formulated after communication with the
investigator.
3.1.1
Dose-limiting toxicity
In accordance with the internationally recognized CTCAE v5.0 toxicity evaluation criteria, the
study DLT was defined as the following toxic reactions related to the study drug VSV-02 occurring
within 4 weeks after the first dose. This study DLT includes, but is not limited to, the following
provisions (fulfillment of any of the following conditions was judged to be a DLT event):

Hematologic toxicity
（1）Grade 4 neutropenia (ANC) lasting ≥7 days;
（2）Febrile neutropenia (ANC <1000/mm3, accompanied by a single measurement of body
temperature >38.3°C or persistent ≥38.0°C for more than 1 hour);

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（3）Grade 4 thrombocytopenia;
（4）Grade 3 thrombocytopenia with bleeding or bleeding events requiring platelet transfusion;
（5）Any ≥grade 3 hematologic toxicity that does not improve to grade 2 or below within 14 days
after standard interventions and supportive measures.

Non-hematologic toxicity
（1）Grade 3 vital organ toxicity, including cardiac, pulmonary, gastrointestinal, hepatic, renal, and
neurologic toxicity; and any other Grade ≥4
（2）Concomitant occurrence of aspartate aminotransferase (AST) or alanine aminotransferase
(ALT) >3 × upper limit of normal (ULN) and total bilirubin (TBIL) >2 × ULN (according to
Hay's Law) without any other reason to explain the elevation; and
（3）Grade ≥3 influenza-like symptoms (including fever, etc.) lasting longer than 7 days after
optimal supportive care;
（4）≥grade 3 cytokine release syndrome
（5）Other ≥Grade 3 non-hematologic toxicity (except simple laboratory test abnormalities that, in
the judgment of the investigator, are not clinically symptomatic and do not require intervention);
（6）Grade 3 TLS with clinical symptoms such as cardiac arrhythmias;
（7）Any death that cannot be clearly attributed to tumor progression or other external causes
(Grade 5 toxicity)

The following are not considered DLT:
Grade 3 rash, nausea, vomiting, diarrhea, or electrolyte disturbances that recover to ≤
grade 2 within 72 hours of optimal medical management;
Grade 3 fatigue ≤7 days;
Grade 3 endocrine disorders adequately controlled with hormone replacement therapy;
Grade 3 tumor lysis syndrome or associated electrolyte disturbances that resolve to ≤
grade 2 within 7 days;
Grade 3 ALT elevation, AST elevation, or alkaline phosphatase (ALP) elevation that
resolves to ≤grade 2 within 7 days;
If a subject develops an investigational drug-related adverse event outside of the above DLT

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criteria, any adverse event judged by the investigator to require termination of treatment will be
discussed by the SMC to determine if it is a DLT.
3.1.2
Maximum tolerated dose
A total of 6 subjects will be required to determine the MTD. if ≤1/6 subjects develop a DLT, that
dose will be considered the MTD; if >1/6 subjects develop a DLT, the previous dose level will be
considered the MTD.
3.1.3
Starting Dose Based on
Toxicology studies in non-clinical studies in rhesus monkeys following 2 cycles of intravenous
administration of 8.0×109PFU/kg and 8.0×1010PFU/kg OVV-01 (QD 7 days, cycle interval 5 days)
followed by a 4-week recovery period showed a maximum non-severe toxicity dose (HNSTD) of 8.0
×1010PFU/kg. converted. Human Equivalent Dose (HED) was 2.58×1010PFU/kg, which corresponds
to a dose of 1.55×1012PFU/subject.
In a GLP toxicology study in tumor-bearing mice, repeated intratumoral and intravenous
injections of OVV-01 for 2 cycles (1 cycle in 7 days, with a 1-day stop in between), followed by a 7-
day recovery period, showed a HNSTD of 3.0×109PFU/mouse (intratumoral) + 1.2×109PFU/mouse
(intravenous). Converted from 20 g of mouse body weight, the HED was 1.22 × 1010PFU/kg
(intratumoral) + 4.88×109PFU/kg, which corresponds to 7.32×1011PFU/subject (intratumoral) + 2.93
×1011PFU/mg (intravenously).
In the completed dose-escalation study (RR-001), 18 patients with advanced solid tumors
received intra-tumoral injections of OVV-01 Injection in four dose groups (6×107 PFU, 6×108PFU,
7×109PFU, and 1.2×1011PFU) administered every two weeks in multiple doses (1 to 6 doses). No
serious adverse events or DLTs related to the study drug occurred in any of the dose groups, and no
MTDs were achieved.
In the ongoing dose-escalation study (RR-008), four patients received OVV-01 Injection via
intra-tumor injection at a dose of 1.2×1011PFU once daily for 6 consecutive days for 2 weeks. As of
the cut-off date (December 16, 2024), there were no DLT events or serious adverse events, and the
treatment demonstrated a favorable safety and tolerability profile. Taken together, these data support
the proposed clinical IV starting dose of 3×1010PFU/subject and the combined starting dose of 3×
1010PFU/mL (intratumoral) + 6×1011PFU/mL (IV) administered multiple times by once-daily dosing.

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3.1.4
Rationale for the dose-escalation rule
Dose group for this study: 3×1010PFU/mL (it.) + 3×1011PFU/subject (iv.). Referring to the
preclinical data, the dose range has covered the clinically effective dose. Upon completion of the dose
group, the SMC assessed whether the dose escalation was newly continued based on outcome
assessment.
The investigator determines the highest dose level that can be tolerated by the subject by closely
monitoring the DLT.
3.1.5
Dose Escalation Settings
The DLT observation period was 4 weeks after the first dose. The first 3 subjects enrolled in each
dose group were incremented to the next dose group if none developed DLT during the DLT
observation period. If ≥2 DLTs occurred in the initial 3 subjects in a dose group, the dose escalation
was stopped or an additional cohort was added to the lower dose group, as recommended by the Safety
Monitoring Committee (SMC). If 1 DLT occurred in the initial 3 subjects, enrollment of 3 additional
subjects at the same dose was continued. If no DLT occurs in the other 3 subjects, the dose is escalated
to the next higher dose group. If ≥1 DLT occurs in 3 additional subjects, dose escalation will be
stopped.
A total of 6 subjects will be required to determine the MTD. if ≤1/6 of the subjects develop a
DLT, the dose will be considered the MTD; if >1/6 of the subjects develop a DLT, the previous dose
level will be considered the MTD.
Dose escalation and stopping rules are summarized in Table 3 of .
Table3 Dose Escalation and Stopping Rules
Number of cases of subjects
experiencing a DLT
Measure
0/3
Escalation to next dose group
1/3
3 additional subjects at the same dose level
1/3 + 0/3
Increment to next dose group
1/3 + ≥1/3
Stop dose escalation and recommend using previous dose level as MTD
NOTE: Treatment of each subject must not raise or lower the dose.
Escalation to the next higher dose group may only occur when the SMC confirms that the current
dose group is sufficiently safe and tolerable. As recommended by the SMC, an intermediate dose level
(3 × 1010PFU/mL) may be explored between the dose group in which 2 DLTs were seen and the
adjacent lower dose group.The SMC will review the safety and tolerability data for each of the dose
groups of VSV-02, as well as other available data, including biodistribution, viral shedding,
pharmacodynamics, and immunogenicity, and then may discuss the appropriate dose escalation and
duration of treatment, and recommend whether to include additional dose groups (which may include

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downward/upward adjustments to the planned dosing, adding additional dose groups, etc.). If both
dose levels proposed in this study are shown to be safe, higher dose levels (e.g., 6×1011PFU/mL) may
be explored, and the exact dose level will be determined by the SMC.
3.2 Study Suspension Rules
The SMC will request that enrollment and dosing be suspended until the situation can be
assessed when the following conditions occur:
Deaths occurring within 30 days of study drug administration (unless clearly due to disease
progression)
Deaths considered by the investigator to be at least potentially related to the study drug
Two Grade ≥4 DLTs in 2 subjects
Any grade 4 hypersensitivity reaction, rapid onset severe allergic reaction
3.3 Definition of study completion
A subject was considered to have completed the study if the subject completed all phases of the
study, including the final visit or the last planned procedure listed in the study schedule.
End of study was defined as completion of the last visit by the final subject, withdrawal of
informed consent by the subject, death, loss of visit, or termination of the study (whichever occurred
earliest).
4
Study Population
4.1 Enrollment Criteria
Subjects must meet all of the following enrollment criteria to be enrolled in this trial:
1.
Voluntarily sign an informed consent form, understand the study and be willing to follow the
protocol and be willing to complete all trial procedures;
2.
Age ≥18 years old at the time of signing the ICF, regardless of gender.
3.
Patients with advanced solid tumors diagnosed after histologic/cytologic examination of the
pathology of the primary and/or metastatic site .
4.
Patients with advanced disease who have failed standard therapy and lack standard treatment.
5.
In principle, subjects must have at least one lesion judged measurable according to RECIST 1.1
criteria, i.e., non-lymph node lesions with a long diameter of ≥10 mm and lymph node lesions
with a short diameter of ≥15 mm according to CT or MRI. and must have injectable tumor
lesions, including superficial lesions, as well as deeper lesions that can be injected under

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ultrasound/CT/ or endoscopic guidance.
6.
Subjects with an ECOG physical status score of 0-2 and an expected survival of not less than 12
weeks.
7.
Adequate organ and hematopoietic function:
Absolute Neutrophil Count (ANC) ≥1.5×109/L;
Platelets ≥75×109/L (no platelet transfusion therapy or thrombopoietin (TPO) therapy within
2 weeks prior to first dose);
Hemoglobin ≥90 g/L (no blood transfusion within 2 weeks);
Serum creatinine ≤1.5 × upper limit of normal (ULN) or endogenous creatinine clearance
(CCr) ≥50mL/min;
Glutamine transaminase (AST) and alanine transaminase (ALT) ≤3.0 × ULN; AST and ALT
< 5 × ULN if patients with liver metastases;
Serum total bilirubin (TBIL) ≤2×ULN;
International Normalized Ratio (INR) ≤1.5×ULN, or Activated Partial Thromboplastin Time
(APTT) ≤1.5×ULN;
8.
Females of childbearing potential must have had a pregnancy test with a negative result within 7
days prior to initiating treatment.
9.
Male and female subjects of childbearing potential must agree to use a reliable method of
contraception for the duration of the trial and for at least 6 months after the last dose.
4.2 Exclusion Criteria
Patients with any of the following are not eligible for enrollment in this study (compassionate use
patients may be treated compassionately on a case-by-case basis at the joint discretion of the PI and
investigator):
1.
Known brain metastases and/or clinical suspicion of brain metastases from the tumor (however,
patients with asymptomatic brain metastases or who have been clinically stable for more than 3
months with local therapy may be enrolled);
2.
Subjects who have had radiotherapy within 2 months of the target lesion;
3.
Subjects with other active malignancies within the previous 5 years. Subjects who have been
completely cured and do not require follow-up therapy are excluded, except for subjects whose
malignancy is within the indications;
4.
The longest diameter of the lesion used for injection is >100 mm;

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5.
Subjects who have participated or are participating in a clinical trial of another drug or medical
device within the previous 4 weeks;
6.
Subjects who are preparing for or have previously received a tissue/organ transplant;
7.
Subjects with human immunodeficiency virus (HIV) infection and AID-related opportunistic
infections within 12 months, or CD4+ T-cell (CD4+) count < 350 cells/uL; Screening Hepatitis B
Surface Antigen (HBsAg) and/or Hepatitis B Core Antibody (HBcAb) positivity with HBV-DNA
above the lower limit of measurability, Screening HCV antibody Positive patients with HCV-
RNA above the lower measurable limit; subjects with positive syphilis spirochete serology;
8.
Subjects requiring antiviral medication during the study or within 5 half-lives of antiviral
medication at the time of first administration.
9.
Subjects requiring therapeutic anticoagulant medication during the study.
10. Subjects with an uncontrolled grade ≥3 active infection of significant clinical relevance according
to CTCAE v5.0;
11. Received antitumor agents such as chemotherapy, radiotherapy, biotherapy, endocrine therapy,
immunotherapy, etc. within 4 weeks prior to the first dose; Received small molecule targeted
therapies and oral fluorouracil analogs within 2 weeks or 5 half-lives (whichever is longer) prior
to the first dose; Received herbal or proprietary Chinese medicines with antitumor indications
within 2 weeks prior to the first dose; Received nitrosoureas or mitomycin C; palliative
radiotherapy to non-target lesions allowed (≥2 weeks prior to first dose);
12. Medication-uncontrolled hypertension or pulmonary hypertension or unstable angina pectoris;
myocardial infarction or bypass or stent surgery within 6 months prior to dosing; history of
chronic heart failure in New York Heart Association (NYHA) criteria grade 3-4; severe
arrhythmias requiring treatment (except atrial fibrillation and paroxysmal supraventricular
tachycardia, which, in the judgment of the investigator, have no effect on the trial), including
QTcF ≥450 ms in men and ≥450 ms in women. 450ms in men and ≥470ms in women (calculated
using the Fridericia formula); cerebrovascular accident (CVA) or transient ischemic attack (TIA)
within 6 months prior to enrollment;
13. Patients with active autoimmune disease or a history of autoimmune disease with possible relapse,
but patients with the following diseases were not excluded and could be screened further
Type 1 diabetes mellitus; and
Hypothyroidism (if controllable with hormone replacement therapy alone) ;Â
Controlled celiac disease .
Skin conditions that do not require systemic therapy (e.g., vitiligo, psoriasis, alopecia

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areata) ;and
Any other condition that will not reoccur in the absence of external triggers ;Â
14. Subjects requiring treatment with systemic corticosteroids (>10 mg /day prednisone or equivalent
dose) or other immunosuppressive medications within 14 days prior to the first dose or during the
study period, except as follows:
Adrenergic replacement steroids (prednisone ≤10 mg / day or equivalent dose of a similar
drug) ;.
Topical, ophthalmic, intra-articular, intranasal, or inhaled corticosteroids.
Prophylactic short-term (≤7 days) use of corticosteroids (e.g., allergy to contrast media) or
for the treatment of non-autoimmune disorders (e.g., delayed hypersensitivity reactions caused by
contact allergens);
15. Subject has a tumor located in a high-risk location (including in a mucosal area, or in close
proximity to the airway, major blood vessels, or spinal cord) that may result in occlusion or
compression due to tumor enlargement, or erosion into major blood vessels due to necrosis, or
encasement of major vascular structures (e.g., carotid arteries), tumors adjacent to important
neurovascular structures, or other tumors deemed unsuitable for intratumoral injections;
16. Subjects will be required to receive any live vaccine during the Screening and Treatment Periods;
17. Subject is allergic to any component of the investigational drug, immunotherapy or related
medications;
18. Subjects with concomitant mental illness, alcoholism, inability to quit smoking, drug abuse or
substance abuse;
19. Pregnant or lactating females;
20. Adverse effects of prior antineoplastic therapy that have not recovered to (CTCAE 5.0) Grade 1
(except alopecia);
21. Serious uncontrollable disease, as determined by the investigator, or the presence of other
conditions that may interfere with receiving treatment in this study and are considered unsuitable
for participation in this study;
22. Other conditions deemed by the investigator to be unsuitable for enrollment.
4.3 Screening Failure
Screening failure is defined as a subject who signed the ICF but did not receive study treatment
for any reason. Necessary information will be collected on subjects with screening failures, including,
but not limited to, demographics, reasons for screening failure/non-compliance with enrollment
criteria, any SAEs and SAE medications that occurred between signing the ICF and withdrawal from

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the study due to screening failure.
Subjects who do not meet the entry criteria may be rescreened. If the rescreening occurs more
than 30 days after the last signed ICF, a new ICF must be signed.The rescreened subject will receive a
new screening number in place of the initial screening number.
4.4 Subject Replacement
Subjects who terminate the study and do not have any imaging after Screening Period imaging
through the end of treatment will be replaced with a new subject, except that subjects who develop
Grade ≥3 toxicity that is definitely or probably related to the study drug as determined by the
investigator will not be replaced.
The decision to replace will be made after discussion and agreement by the Principal Investigator
(PI), SMC.
4.5 Termination of Treatment for Subjects
Subjects will be considered for permanent termination of treatment upon occurrence of any of
the following conditions

Subject develops DLT during the DLT observation period.

Subject develops clinically unstable disease progression as determined in accordance with
RECIST 1.1.

The subject develops any AE or complication that may result in discontinuation of study
treatment for more than 6 weeks, or the investigator deems it necessary to terminate study
treatment.

The subject experiences a clinically significant deterioration in health status that warrants
discontinuation of treatment.

The subject is unfit to continue treatment for other medical reasons (e.g., pregnancy).

The subject requests termination of treatment for personal reasons.

The subject misses a visit.
Reason for treatment termination must be documented in the eCRF. Termination of treatment
does not mean withdrawal from the study and all remaining study processes must be completed in
accordance with the study protocol.

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4.6 Subject Withdrawal from Study
Subjects have the right to request withdrawal from the study at any time and may be withdrawn
from the study for safety, behavioral, or administrative reasons at the discretion of the investigator.
Subjects must terminate study medication and withdraw from the study when any of the
following conditions occur
1. Pregnancy
2. Obvious noncompliance with the study intervention
3. Development of any clinical AE, laboratory test abnormality, or other disease or condition that
makes continued participation in the study contrary to the subject's best interest
4. Need for anticancer treatment outside of the study protocol
5. Subject is unable to receive VSV-02 administration for 6 consecutive weeks. If the
disappearance of an injectable tumor lesion results in termination of study dosing, in which
case it is the investigator's decision whether the subject will continue to receive VSV-02
and/or continue to participate in the study
6. Occurrence of what the investigator, after discussion, unanimously recognizes as a significant
protocol violation
7. Withdrawal of informed consent
8. Termination of the study by the investigator
9. Termination of the study by the local health regulatory authority, regulatory agency or
Institutional Review Board/Independent Ethics Committee (IRB/IEC)
If the subject decides to withdraw from the study, or if the investigator believes that the subject
should withdraw from the study: the collaborating research medical monitor must be notified within
24 hours, and the reason for withdrawal must be documented in the subject's medical record and CRF.
The investigator must try to follow all subjects for safety until the follow-up assessment or study drug-
related toxicity resolves, returns to baseline, or is judged to be irreversible, whichever occurs latest.
Reasons for subject termination or withdrawal from the study must be documented in the eCRF.
4.7 Research Intervention Abort/Terminate
This trial has the potential for early termination under certain circumstances; circumstances that
may terminate a clinical trial include, but are not limited to:

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（1）The occurrence of a serious adverse event due to the test drug at the subject dose that, in
the judgment of the investigator, may result in a serious safety risk to other subjects, shall result in
termination of the trial;
（2）If the Investigator or Collaborator becomes aware of new research evidence suggesting
that there is a serious safety concern with the trial drug product that is not included in the Drug
Formulary/IB and that may result in harm to subjects if the clinical trial is continued, the Collaborator
and the Investigator jointly evaluate and decide whether to terminate the trial;
（3）Significant deviations or human errors are found at the end of the trial implementation
process, which seriously affects the quality of the trial and makes it difficult to achieve the purpose of
the trial;
（4）The administrative authority requires the termination of the trial;
（5）The partner requests to terminate the trial under the premise of fully protecting the rights
and safety of the subjects (e.g., financial reasons, management reasons, etc.).
When the research intervention is discontinued, the follow-up study procedures should be
completed in accordance with the provisions of the trial protocol. In the event of a clinically
meaningful change in a subject after enrollment (including, but not limited to, a change that deviates
from baseline levels), the investigator or qualified designee will determine whether a change in subject
management is warranted. Any clinically relevant new findings will be reported as an adverse event
(AE).
4.8 Loss of Subjects to Visit
A subject was considered "lost" if he or she was unable to attend a scheduled visit and could not
be contacted by Research Center staff. A lost visit was defined as a situation in which the subject could
not be reached after 2 or more non-consecutive phone calls or through other contact information
provided by the subject. A subject is considered a lost visit if he or she cannot be contacted after taking
the above steps. These contact records should be documented in the subject's medical record or study
documentation.
5
Research Intervention
5.1 Study Drug
5.1.1
Description of study drug
Study Drug
VSV-02 Injection
Specification
1mL/vial, 3.0×1010PFU/mL
Storage and
transportation
conditions
≤-70°C Storage and transportation.
Manufacturer
Shanghai Rongrui Pharmaceutical Technology Co.

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Supplier
Shanghai Rongrui Pharmaceutical Technology Co.
5.1.2
Study drug dosing regimen
VSV-02 injection was administered intravenously + intratumorally at a dose of 3×1010PFU/mL
(it.) + 3×1011PFU (iv.) on day 1 (D1) of each cycle, with a maximum of 6 cycles per 3-week treatment
cycle, and intravenous and intratumorally on the same day.
Patients who are screened for eligible enrollment will undergo systematic safety observations
within 6 weeks of the first dose, and if the patient does not develop a DLT, the dose will be
determined to be the Maximum Tolerated Dose (MTD) and the Recommended Phase II Dose (RP2D).
If DLT is observed in 1 patient, 3 subjects will be added to the cohort, and if DLT is observed in ≥2
patients, the new cohort will be added at a lower dose as recommended by SMC.
If DLT occurs during the DLT observation period, VSV-02 administration will be discontinued.
If DLT does not occur, treatment will continue until disease progression, the subject develops
intolerable toxicity, the subject withdraws informed consent, the subject dies, is lost to visitation, the
investigator determines that it is in the patient's best interest to terminate treatment, or 6 consecutive
cycles of administration have been completed, whichever occurs earliest.
Intratumoral injection administration:
The volume of intratumorally injected VSV-02 was determined based on the size of the tumor
lesion and was given to the maximum volume possible according to the guidelines in the table below.
The investigator evaluated the size of the subject's injected lesion within 24 h prior to each injection to
determine the volume of study drug to be injected. The total injection volume of all lesions per subject
per dosing day was not to exceed 10 mL.
Table4 Guidelines for Injection Volume of VSV-02 Injection Based on Tumor Size
Lesion size (longest
diameter)
Injection volume
≤0.5 cm
0.5 mL
>0.5 cm and ≤1.0 cm
1.0 mL
>1.0 cm
For every 1.0 cm increase in lesion size (rounded) from 1.0 cm, increase the injection
volume by 1.0 mL from 1.0 mL (e.g., 3.0 mL for a 3.0 cm lesion).
Injection:
（3）
It may not be possible to inject all lesions at a time; prioritize the largest lesion and inject other lesions
according to the size of the lesion until the maximum delivery volume is reached. The same lesion should be
injected each time unless the injected lesion shrinks to the point where it cannot receive the injection.

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If there is residual drug available because the tumor lesion has shrunk, a new lesion may be selected for
injection.
Intravenous Administration:
Each subject will receive a fixed dose intravenously, prepared as a 100 ml solution using an
intravenous bag of 100 ml saline (0.9% sodium chloride injection), and administration can be
completed in 30 minutes (±10 minutes).
5.1.3
Precautions for administration
1) Inject a lesion that is measurable and capable of receiving the injection either directly or under
ultrasound or CT guidance or endoscopy;
2) Full dose uniformity and complete dispersion is achieved by using a single insertion point,
pulling the needle back within the lesion without withdrawing from the lesion, along 2-4
tracks as far as the radial extent of the needle allows the lesion to be reached. If the lesion is
larger than 5 cm, 2 insertion points of the needle radial may be used;
3) When the needle is removed, it is withdrawn slowly from the lesion and should be held briefly
before completely withdrawing from the lesion to avoid leakage of the injected fluid at the
insertion point;
4) Use a new needle any time the needle is completely withdrawn from a lesion and when
injecting in a different lesion;
5) Injections at special sites follow clinical practice or are at the discretion of the investigator.
5.1.4
Principles of dosing adjustments
VSV-02 dose should not be adjusted during the DLT observation period. VSV-02 administration
should be terminated if any DLT occurs.
During the study period, the investigator will take necessary safety measures for subjects based
on AE level (as determined by NCI-CTCAE v5.0) and clinical presentation. Possible measures to be
taken are shown below:
For ≤Grade 2 AE, continue VSV-02 administration whenever possible. The investigator will
consider administering the appropriate interventional therapy based on the clinical situation.
Suspend VSV-02 administration for Grade 3 AE or Grade 2 AE of ≥7 days duration. The
investigator will decide to continue or terminate treatment based on the subject's recovery.

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For Grade 4 AE, terminate VSV-02 administration immediately.
For grade ≥3 asymptomatic laboratory test abnormalities, close observation will be given if
the investigator determines that there is no clinical significance. The investigator will decide
whether to suspend dosing or provide appropriate interventional therapy based on the
outcome of these abnormalities.
5.2 Preparation/Handling/Storage/Duties of Study Drugs
5.2.1
Receipt and inventory of drug
The partner is responsible for shipping the study drug to the study center and the
investigator/pharmacist signs to acknowledge receipt.
The study medication will only be used for this study and will only be administered by a person
authorized by the investigator to do so. The investigator/pharmacist responsible for drug
administration dispenses, recovers, and destroys the study drug according to study procedures and
keeps accurate records.
5.2.2
Dosage form, appearance, packaging and labeling
VSV-02 Injection (for clinical research use only)
Study protocol number: Bottle no:
Product lot number:
Product Specification: 3 × 1010PFU/mL, 1 mL/branch
Production date: MM/DD/YYYYY
Expiry date: 36 months (tentative)
Storage condition: ≤-70 ℃, keep away from light.
Mode of administration: Intratumoral injection, Intravenous injection
Manufacturer: Shanghai Rongrui Pharmaceutical Technology Co.
5.2.3
Product storage and stability
The research center should strictly comply with the provisions of GCP "Management of
experimental drugs", and at the same time, store and manage the research drug according to the
storage conditions provided by the sponsor, ≤-70 ℃for storage and transportation.
The investigational drug must be stored in a safe area and accessible only to authorized
personnel before distribution to subjects.

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5.3 Destruction and Recall of Investigational Drug
Destruction and retrieval of investigational drugs will be conducted in accordance with the
relevant Standard Operating Procedures (SOPs) of the research center. The investigator must ensure
that all trial medications are used only for the subjects enrolled in the clinical trial, that any remaining
medications after opening should be destroyed, and that any remaining medications that have not been
opened for use should be returned to the sponsor, and that the trial medications should not be passed
on to any non-clinical trial participant. Supervisors are responsible for supervising the process of
supplying, using, storing, and disposing of leftover drugs for clinical trials.
5.4 Adherence to the study intervention
To ensure treatment adherence, dosing will be supervised by the investigator or his/her assistant.
The exact time of administration and dose of medication will be recorded on the eCRF. Reasons for
delayed dosing, medication reduction, omission, and termination should also be recorded in the eCRF.
Adherence will be further confirmed based on study drug dispensing, drug preparation, drug return,
study case and eCRF records. Circumstances affecting subject compliance (e.g., side effects of
treatment, perceived lack of antitumor activity, subject's unwillingness to comply with study
requirements, etc.) affecting the decision to discontinue treatment should also be noted in the eCRF at
that time. Subject compliance with the treatment and regimen refers to voluntary compliance with all
aspects of the regimen, including compliance with all tests required for safety assessment and imaging
for tumor assessment. Subjects who do not return for follow-up visits may be terminated from the
study at the discretion of the Principal Investigator.
5.5 Combination of medications and treatments
All comorbid medications and treatments from the time the subject signs the informed consent to
28 days after the last dose (or until the subject starts a new antitumor therapy) are to be documented in
detail in the electronic case report form (eCRF) with the reason for the medication.
5.5.1
Dispensing of Study Drugs
The study drug is provided by the sponsor and distributed to the research center on a scheduled
basis. Upon receipt of the study drug, the designated personnel at the research center will be required
to verify the shipping temperature of the study drug, count the drug, sign for the drug after verifying
that it is correct, and the relevant records should be retained in the investigator's folder, as well as
record the storage temperature of the drug on a daily basis, and record the items in the inventory sheet:
date of receipt of the study drug, number of doses, batch number, number of doses dispensed, and the
amount of the drug remaining in the inventory. Dispensing of medication during the study will be

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conducted by a member of the study team. This member will be required to ensure and document that
the subject receives the medication as scheduled and record the number and date of medications
dispensed and recalled in the original medical record. Investigators are expected to use study
medications within the framework of the clinical study as required by the protocol.
5.5.2
Prohibited Foods, Drugs, and Treatments
1) Concomitant use of any anticancer therapy (chemotherapy, immunotherapy, biologics,
extensive radiotherapy, hormonal therapy, targeted therapy, surgery, interventional therapy,
device therapy), investigational therapy, or approved therapy.
2) Immunosuppressive agents, except for the treatment of immune-related adverse events (irAE).
3) Systemic corticosteroid therapy with immunosuppressive effects, except for the short-term
treatment of injection site reactions, irAE, or adrenal insufficiency requiring hormone
replacement therapy. If systemic corticosteroids are used, they must be tapered prior to the
next study treatment and the daily dose must not exceed 10 mg prednisone or equivalent. If
the daily dose exceeds 10 mg prednisone, study drug administration should be suspended.
4) No herbal medications approved for the treatment of cancer should be used.
5) Live or live attenuated vaccines should not be administered throughout the study period.
5.5.3
Permitted medications and treatments
The following medications are permitted during the study, as appropriate
（1）Long-term medications required by co-morbidities (e.g., hypertension, diabetes, etc.);
（2）Topical, ocular, intra-articular, intranasal administration, and inhaled corticosteroids
(minimal systemic absorption) are allowed for subjects during the study. Short-term (<1 week) use of
corticosteroids is allowed for prophylaxis (e.g., contrast allergy) or for treatment of non-autoimmune
conditions (e.g., delayed allergic reactions due to contact allergens);
（3）Symptomatic supportive treatment for toxic reactions to the drug or for control of tumor
symptoms, in a manner that protects the interests and safety of the subject, by the investigator.
（4）Patients with bone metastases may receive bisphosphonate therapy. Palliative small-area
(radiotherapy area must be <5% bone marrow area) radiation therapy is permitted if painful bone
metastatic lesions are not effectively controlled by systemic therapy or local analgesia. Local radiation
therapy should be avoided as much as possible during the DLT observation period.

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6
Study Steps
6.1 Screening Period
Unless otherwise specified, screening assessments will be completed within 28 days prior to the
first dose of VSV-02. For the protection of the subject, if the required screening or assessment has
been completed prior to the signing of the ICF and is completed within the time frame specified in the
protocol, it does not need to be repeated.
To ensure that subjects meet the enrollment criteria for this study, the following study processes
must be completed during the Screening Period (D-28 through D-1, including the Baseline Period [D-
7 through D-1]):
1) Informed Consent: sign name and date on ICF.
2) Review of Inclusion/Exclusion Criteria: if the first dose is more than 7 days from the
Screening Period, reassessment will be done at the Baseline Period.
3) Demographic information contains year of birth, gender, ethnicity.
4) Collection of medical, prior treatment, allergy, personal, and family history: includes history
of tumor-related medical conditions and prior treatments, non-tumor-related medical
conditions and prior treatments, food and drug allergies, smoking, alcohol consumption, and
substance abuse.
5) Physical examination: including general condition, head and neck, lymph nodes, skin, chest,
abdomen, musculoskeletal system (including extremities and spine), height and weight.
Receive the results of an examination at our study center within 7 days prior to the first dose.
6) Vital signs exam: including blood pressure, pulse/heart rate, respiration, and temperature.
Accept results from this study center within 7 days prior to the first dose.
7) ECOG score: reassessed at baseline if the first dose was given more than 7 days before the
screening period.
8) Laboratory tests, including routine blood tests, blood biochemistry tests, coagulation tests,
thyroid function tests, and routine urine tests. Receive results of routine blood, blood
biochemistry tests, coagulation function tests, and routine urine tests from our study center
within 7 days prior to the first dose of drug. Accept results of thyroid function tests from this
study center within 14 days prior to the first dose.

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9) Virologic examination, including Hepatitis B V (HBsAg, HBsAb, HBeAg, HBeAb, HBcAb),
HCV antibody, HIV antibody, CD4+ T-cell count, and syphilis serologic test; if HBsAg (+)
and/or HBcAb (+), and/or HCV antibody (+) are examined in the screening period,
continued examination of HBV-DNA and/or HCV-RNA for further screening.
10) Perform a blood pregnancy test in female subjects of childbearing potential within 7 days
prior to the first dose.
11) 12-lead electrocardiogram: repeat at baseline if first dose is more than 7 days from screening.
12) Echocardiography: performed within 28 days prior to first dose.
13) Enhanced CT or MRI is preferred for tumor imaging, and plain CT is available for contrast-
allergic subjects, but the method of examination should be consistent, and whether to apply
PET-CT examination is decided by the investigator; the sites of imaging examination in the
Screening Period include the chest, abdomen, pelvis, brain, and systemic bone, and the
method of imaging examination in the subsequent cycles should be the same as that in the
Baseline Period. If the patient has already had an imaging study within 28 days prior to the
first dose and meets the requirements, the study may not be repeated.
14) Paraffin sections of tissue specimens will be provided by the subjects, or if this is not
possible, the investigator will obtain tumor tissue and normal tissue adjacent to the tumor by
fine-needle puncture before the first treatment. Tissue sample collection was voluntary.
15) AEs/SAEs and concomitant medications were recorded from the time the ICF was signed.
6.2 Treatment Period
Screening-eligible subjects were administered starting on Week 1, Day 1 (W1D1) and every 3
weeks as a treatment cycle, with intravenous and intratumoral injections administered on the same day.
Subjects were administered according to a fixed dose until disease progression, intolerable toxicity in
the subject, withdrawal of informed consent by the subject, death of the subject, loss to follow-up,
termination of treatment as deemed by the investigator to be in the best interest of the patient, or 6
cycles of study drug administration had been completed, whichever occurred earliest.
1) VSV-02 injection was administered directly or under ultrasound/CT guidance at single or
multiple sites throughout the tumor body, with a maximum injection volume of no more than
10 mL.The investigator should select the appropriate injection lesion according to the
injection volume guidelines.
2) Physical Examination: one guided physical examination prior to the first dose of each cycle.

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3) Vital signs: within 2 h before, 2 h (±15 min) and 4 h (±30 min) after administration of C1D1,
within 2 h before administration of C1 other, within 2 h before the first dose of each cycle of
C2~C6.
4) ECOG score: once before the first dose of each cycle.
5) Laboratory tests (including blood routine, blood biochemistry test, coagulation function test,
urine routine):
Blood routine: within 48h prior to the first dose of each cycle. The investigator may
increase the frequency of tests according to clinical indications.
Blood biochemistry, routine urine and coagulation tests: within 48h before the first dose of
each cycle.
6) Urine pregnancy every 4 weeks during the treatment period. In case of a positive urine
pregnancy test, a blood pregnancy test will be performed.
7) 12-lead electrocardiogram: within 48 h prior to the first dose of each cycle.
8) Biodistribution and time points for viral shedding, biomarker and cytokine blood sample
collection are listed in Table 2 .
9) Immunogenic blood collection within 2 h prior to the first dose of each cycle.
10) Tumor efficacy evaluation: Tumor efficacy was assessed every 6 weeks (±7 days) after the
first dose of drug, with examination of the lesion site only (except in cases of suspected
metastasis) and bone scan (only during the treatment period when relevant signs were
present). Unscheduled imaging may be performed if disease progression is suspected (e.g.,
worsening of symptoms).
11) Tissue specimen collection is performed after the last treatment session. Tissue specimen
collection is voluntary.
12) AE and concomitant medications are recorded.
6.3 End of Treatment (EOT) Visit
Subjects ending treatment or withdrawing early from the study should have an EOT visit within
7 days of being informed of the end of treatment. If the EOT visit is within the safe follow-up time
window, no re-examination is required. For safety reasons, the investigator may conduct additional
visits as needed (i.e., unplanned visits) if the subject develops any AEs, has abnormal laboratory test
results, or has any discomfort during the study. The investigator should document the details of each

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unplanned visit in the unplanned visit section of the original medical record and in the eCRF.
Processes to be completed for end of treatment, early withdrawal from the study, or unplanned
visits include but are not limited to
1) Physical examination
2) Vital signs
3) ECOG score
4) Laboratory tests (including routine blood tests, blood biochemistry tests, coagulation tests,
thyroid function tests, and urinalysis)
5) Pregnancy test
6) 12-lead electrocardiogram
7) Echocardiogram
8) Imaging: Imaging does not need to be repeated at the EOT visit if the interval between the
EOT visit and the previous imaging is no more than 4 weeks.
9) Biodistribution and viral shedding sampling
10) Immunogenic blood collection
11) Documentation of AE and concomitant medications
Note: Unscheduled visits may be scheduled by the investigator depending on the status of the subject.
6.4 Safety Follow-Up
A safety follow-up visit is required 28 days (±7 days) after the last dose. For subjects who
discontinued treatment due to disease progression, safety data were collected within 7 days of
notification/establishment of subject discontinuation. If the subject receives other antitumor therapy
outside of the protocol within the 28-day (±7-day) timeframe of safety follow-up, no subsequent study
data will be collected for safety follow-up and survival follow-up.
The following process will be performed:
1) Physical examination
2) Vital signs
3) ECOG score

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4) Laboratory tests (including routine blood tests, blood biochemistry tests, coagulation tests,
thyroid function tests, urine routine)
5) Pregnancy test
6) 12-lead electrocardiogram
7) Immunogenic blood collection
8) Evaluation of biodistribution and viral shedding
9) Documentation of AE and concomitant medications
If the proposed end-of-treatment visit is close to the safety follow-up visit, the investigator may
assess whether to perform additional safety assessment tests.
Note: ADRs are to be followed until ADRs stabilize or return to ≤Grade 1, or baseline levels, unless
the subject withdraws informed consent, dies, is lost to follow-up, or receives other antitumor therapy
other than that specified in the protocol.
6.5 Survival Follow-Up
Subjects who discontinued treatment were followed every 12 weeks until the subject withdrew
informed consent, died, lost to visit, received other antitumor therapy than that specified in the
protocol, or the study was completed (whichever occurred earliest), with telephone follow-up allowed.
After the subject has completed 12 cycles of multiple dosing, if the investigator judges that the subject
may still benefit from continuing VSV-02 treatment, he/she may apply to the collaborator to continue
the treatment, but he/she must sign a separate informed consent form, which is based on the actual
condition of the patient, and is prepared after communication with the investigator.
Subjects who have terminated treatment and have not progressed (and have not been treated with
any other antitumor therapy other than that specified in the protocol) will be required to return to the
hospital every 12 weeks for oncologic efficacy assessment follow-up; subjects who have progressed
(and have not been treated with any other antitumor therapy other than that specified in the protocol)
will be required to undergo survival follow-up only once every 12 weeks with an option of telephone
follow-up; if they receive any other antitumor therapy other than that specified in the protocol, follow-
up visits will be discontinued. discontinue follow-up. The time window for each assessment is ± 7
days.
7
Study Evaluation
7.1 Safety Evaluation

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7.1.1
General information
Demographics: age, gender, ethnicity.
Medical/treatment history: including history of prior illnesses and history of other illnesses and
treatments; prior medical history includes histologic/pathologic diagnosis, date of diagnosis, staging,
and prior therapeutic measures taken. Ask and record the subject's history of other diseases and
treatments.
7.1.2
Adverse events
All AEs and SAEs, whether or not related to the study drug, occurring from the start of ICF
signing to 28 days (±7 days) after the last dose will be recorded. AEs will be graded using CTCAE
v5.0 and recorded throughout the study period.
7.1.3
ECOG Physical Fitness Score
The ECOG Physical Fitness Status Rating Scale is shown below.
ECOG Physical Fitness Status[13]
Level
ECOG
0
Complete normal mobility, no difference in mobility from before the onset of the disease
1
Able to walk freely and engage in light physical activities, including general housework or office work,
but unable to engage in heavier physical activity
2
Able to walk freely and take care of oneself, but incapable of work, and can get up and move around not
less than half of the time during the day.
3
Can only partially take care of themselves, and are bedridden or wheelchair-bound for more than half of
the day.
4
Completely incapacitated, bedridden and unable to take care of themselves.
5
Death
7.1.4
Laboratory tests specifically include the following:
1. Routine blood: including white blood cell count, neutrophil count, eosinophil count, basophil
count,
lymphocyte
count,
erythrocyte
count,
reticulocyte,
erythrocyte
hematocrit,
hemoglobin, platelet count.
2. Blood biochemistry: including (liver function) serum alanine aminotransferase, aspartate
aminotransferase, albumin, total bilirubin, direct bilirubin, alkaline phosphatase, gamma-
glutamyltransferase, (renal function) creatinine, urea/urea nitrogen, uric acid, (electrolytes)
potassium, sodium, chloride, calcium, magnesium, phosphorus.
3. Urine routine: including protein, glucose, white blood cells, red blood cells, occult blood. If
there are clinical indications, 24 h urine protein quantification should be added.

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4. Coagulation
function:
including
international
normalized
ratio,
activated
partial
thromboplastin time, prothrombin time, fibrinogen;
5. Thyroid function: including T4, T3, FT3, FT4, TSH, TG, TGAb, TPOAb;
6. Virological testing: the test items include Hepatitis B two-half pairs, which include Hepatitis B
Virus Surface Antibody (HBsAb), Hepatitis B Virus Surface Antigen (HBsAg), Hepatitis B
Virus e Antigen (HBeAg), Hepatitis B Virus e Antibody (HBeAb), and Hepatitis B Virus
Core Antibody (HBcAb), and are required for HBsAg positivity and/or HBcAb positivity.
Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA); Hepatitis C Virus (HCV) Antibody,
plus HCV-RNA if HCV antibody positive; HIV Antibody, CD4+ T-cell count; Syphilis
serologic testing.
7.1.5
Vital Signs
Tests included: including temperature, pulse/heart rate, respiratory rate, and blood pressure
(systolic and diastolic), which was checked and recorded in the seated position starting after the
subject had rested for at least 5 minutes. The site of blood pressure measurement at baseline and after
drug administration needs to be on the same side of the arm as far as possible. The investigator may
decide to increase the frequency of vital sign examinations based on the subject's clinical condition.
7.1.6
Physical examination includes a complete physical examination (general condition, head and
neck, lymph nodes, skin, chest, abdomen, musculoskeletal system (including limbs and spine), height
and weight) and a symptom-oriented physical examination.
7.1.7
12-lead electrocardiogram
The ECG was completed according to the flow of the protocol, and it was necessary to verify
that the system was calibrated and that the time recorded on the ECG corresponded to the true time
before starting the ECG.
Subjects should rest for at least 10 minutes before performing the ECG and complete the
examination in a flat lying position. The ECG report is required:
−Heart rate
−Rhythm (sinus rhythm or pacing rhythm)
−PR interval (msec), RR (msec), QRS (msec)

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−QT interval (msec), QTcF (msec)
During the entire study period (including the screening period, treatment period, safety
observation period, etc.), those with abnormal tests may be retested at the judgment of the investigator,
and the next retest is required to be performed at intervals of 10 (±5) min, for a total of 3 times, and
the average value is calculated.
7.1.8
Echocardiography
Echocardiography was performed during the screening period and at the end of treatment or
early exit visit to measure left ventricular ejection fraction and related indices of cardiac function.
Unscheduled examinations can be arranged if required during the treatment period. Examination
reports are required to provide: output per beat (SVmL), left ventricular ejection fraction (LVEF%),
cardiac output (CO L/min), and left ventricular short-axis shortening (FS%).
7.2 Validity Evaluation
7.2.1
Criteria for effectiveness evaluation
Tumor response will be assessed every 6 weeks after the first dose and at the end of study (EOT)
visit. Assessed by the investigator according to RECIST 1.1[14] . Lesions are preferably followed
throughout the study period using the same imaging modality as at baseline evaluation.
Pseudoprogression may be observed in some subjects on their first few imaging examinations
after receiving immunotherapeutic agents such as PD-1/PD-L1 inhibitors, mainly because of the
following reason: immunotherapeutic agents are able to elicit immune cells infiltrating into and around
the tumor to respond to the drugs, resulting in the simultaneous detection of both the tumor as well as
the tumor-surrounding immune cells on the imaging examinations. As a result, the examination results
may show a significant increase in tumor size or the appearance of new tumor foci, but in reality, the
tumor size may be decreasing. Therefore, in this study, after the first imaging disease progression in a
subject, as determined by the investigator according to RECIST 1.1 criteria, subjects were allowed to
continue to receive VSV-02 if the investigator determined that no deterioration in the subject's clinical
status had occurred and it was believed that there might be a clinical benefit to continue treating the
subject. However, for such subjects, another tumor evaluation should be performed at least 4 weeks
later to confirm disease progression according to iRECIST[15] . After the investigator assesses a
subject for first disease progression, if the subject develops grade ≥3 toxicity, the subject may not
continue on study treatment. Upon confirmation of disease progression, the subject should discontinue
treatment and receive an end-of-treatment visit.

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Clinical stability is defined as the absence of clinically significant signs and symptoms
suggestive of disease progression (including abnormal laboratory test values), no reduction in Eastern
Cooperative Oncology Group (ECOG) Physical Status Score, absence of rapid disease progression,
and absence of progressive tumors (e.g., spinal cord compression) at important anatomical sites that
would require other urgent medical intervention. Subjects judged to be clinically unstable should
terminate trial treatment since the first imaging disease progression evaluated by the investigator and
not require repeat imaging to confirm disease progression according to iRECIST. At the end of study
treatment, if the last tumor imaging evaluation was performed within the last 4 weeks, it may be
omitted upon evaluation by the investigator.
7.2.2
Definition of efficacy evaluation endpoints
The efficacy endpoints for this study will be evaluated according to RECIST 1.1 and are defined
below:
1) Objective remission rate (ORR): proportion of subjects achieving CR or PR.
2) DCR: Proportion of subjects achieving CR, PR or SD.
3) DOR: For subjects achieving objective remission, DOR is the time between the first recorded
objective tumor remission (CR or PR) and the first recorded disease progression or death
from any cause, whichever occurs earlier.
4) PFS: time from first study treatment to the date of first documented disease progression or
death due to any cause, whichever occurs earlier.
5) OS: time from first study treatment to date of death from any cause.
7.3 Biodistribution and viral shedding evaluation
Biodistribution of VSV-02 was assessed by detecting viral gDNA levels in blood using a real-
time quantitative poly synthase chain reaction (qPCR) assay. Viral shedding was evaluated by
detecting viral gDNA levels in urine, feces, saliva and injection site swabs. Samples will first be
analyzed by qPCR to determine the detectability of viral gDNA. If the qPCR assay is positive, the
biodistribution and shedding samples will be tested for TCID50 to determine viral infectivity.
7.4 Immunogenicity Assessment
To assess changes in the production of anti-VSV-G antibody (IgG) antibodies in subjects
following treatment. The potential immunogenicity of VSV-02 was assessed by determining the
concentration of ADA before and after administration. Evaluate only subjects who have received at

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least one dose of VSV-02 and have provided a baseline sample and at least one post-treatment sample.
7.5 Biomarker and Cytokine Evaluation
7.5.1
Analysis of Tissue Samples
During the screening period, paraffin sections of tissue specimens will be provided by the
subjects, or the investigator will obtain specimens of tumor tissues and normal tissues adjacent to the
tumors by fine-needle puncture before the first treatment; during the treatment period, the above tissue
specimen collection will be performed after the last treatment for the following items: (the process of
tissue specimen collection is voluntary for the subjects, and the specific items can be carried out
according to the study needs and the actual situation of the study).
1) Analysis of NY-ESO-1 antigen expression by immunohistochemistry (IHC);
2) Analyze the expression of PD-L1 by IHC method;
3) After the tissue cells were resuspended, flow cytometry was used to detect the expression of
immune cells infiltrating CD4+ T cells (CD3+ CD4+), CD8+ T cells (CD3+ CD8+), NK cells (CD3-
CD16+CD56+), monocytes (CD14 high CD16 low) and macrophages (CD14 low CD16 high). The
expression of
4) Detect the distribution of VSV-02 virus particles in tissues by qPCR.
7.5.2
Blood sample analysis
Test items and sample requirements (specific test items can be performed according to the
needs of the study and the actual situation of the study):
Detection of NY-ESO-1 antigen by ELISA;
Plasma cytokines: IL-6, IL-2, IL-8, IL-10, IL-12p70, TNF-α, IFN-γ, GM-CSF, IL-5, IL-15 by
MSD;
Lymphocyte subpopulations were analyzed by flow cytometry: CD3+ T cells, the proportion
of CD4+ T cells (CD3+ CD4+), CD8+ T cells (CD3+ CD8+) and the absolute cell number;
Expansion of lymphocyte subsets was analyzed by flow cytometry: proportion of CD27-,
CCR7- subsets expanded in CD3+, CD8+, CD45RO+, CD45RA- cell subsets; blood samples
were shared with lymphocyte subsets.
8
Adverse Events and Serious Adverse Events
8.1 Adverse Events

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8.1.1
Definition of adverse events
Adverse events (AEs) are all adverse medical events that occur after a subject receives an
investigational medication, which may be manifested as signs and symptoms, disease, or abnormal
laboratory tests, but are not necessarily causally related to the investigational medication.
AEs include, but are not limited to, the following: (1) exacerbation of a pre-existing (prior to
entry into the clinical trial) medical condition/disease (including exacerbation of symptoms, signs,
laboratory test abnormalities); (2) new onset of any adverse medical condition (including signs,
symptoms, newly diagnosed disease); and (3) abnormal clinically significant laboratory test
values/results.
Definite signs or symptoms of tumor progression should not be recorded as an adverse event
unless they are more severe than expected or the investigator believes that the tumor progression is
related to the test drug or study procedures. If a new primary malignancy develops, such events should
be considered adverse events.
8.1.2
Severity of Adverse Events
Grading refers to the severity of the adverse event. Determine the severity of the AE based on the
U.S. Department of Health and Human Services CTCAE 5.0 criteria. If an AE not listed in the table
occurs, grade the severity of the AE according to Table 5 .
Table5 Adverse Event Severity
Grade
CTCAE Situation
1
Mild; asymptomatic or mild; seen only clinically or diagnostically; no treatment required.
2
Moderate; requires minor, localized or non-invasive treatment; age-appropriate instrumental daily
living
activity limitations*.
3
Severe or medically significant but not immediately life-threatening; results in hospitalization or
prolonged hospitalization; disabling; self-instrumented limitations in activities of daily living**.
4
Life-threatening; requires urgent treatment.
5
Death associated with an adverse event.
CTCAE = Common Criteria for the Evaluation of Adverse Events
*:Instrumental activities of daily living refer to cooking, purchasing clothing, using the telephone, and managing
money.
**:Autonomous activities of daily living refers to bathing, dressing and undressing, eating, toileting, taking
medications, etc., and was not bedridden.
8.1.3
Determination of Adverse Event Relevance to Trial Medications
The investigator must assess the relationship between the event and the study intervention based
on the temporal relationship between the AE and the study intervention and clinical judgment. The
following categories will be used to rate the degree of certainty of causality. The causal relationship

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between the investigational product and the event must always be viewed with skepticism in clinical
trials. Drug-related AEs will be defined as probably related, probably related, or definitely related.
• Positively Related - Clear evidence of a causal relationship and other possible factors can be
ruled out. Clinical events (including abnormal laboratory test results) have a reasonable
temporal relationship to the administration of the study intervention that cannot be explained
by complications or other drugs or chemicals. The response after cessation of the
investigational intervention (de-stimulation) should be reasonably explainable from a clinical
standpoint. The event must have a clear pharmacological or phenomenological profile and
should be confirmed by a re-priming procedure if necessary.
• Likely related - evidence of causality, unlikely to be influenced by other factors. The clinical
event (including abnormal laboratory test results) occurs within a reasonable time after the
implementation of the study intervention, is unlikely to be attributable to complications or to
other drugs or chemicals, and produces a response that can be reasonably explained from a
clinical perspective after discontinuation of the medication (de-priming). There is no need to
provide re-priming information in order to meet this definition.
• Possibly Related - There is some evidence of causation (e.g., the event occurred within a
reasonable period of time after administration of the test drug). However, other factors may
have contributed to the event (e.g., the subject's clinical condition and other comorbid events).
Although an AE may only be rated as "possibly related" shortly after discovery, it may be
flagged as requiring more information and subsequently upgraded to "probably related" or
"definitely related" as appropriate. ".
• Possibly unrelated - The temporal relationship between the clinical event (including
abnormal laboratory test results) and the study intervention suggests that a causal relationship
is unlikely (e.g., the event did not occur within a reasonable time after the study intervention)
and that other drugs or chemicals or the underlying disease provide a reasonable explanation
(e.g., the subject's clinical condition, other comorbid treatments).
• Definitely Unrelated - The AE is completely unrelated to the implementation of the study
intervention and/or there is evidence that the event is definitely related to another etiology.
There must be another clear etiology documented by the investigator.
8.1.4
Collection of Adverse Events
A consistent, non-induced questioning method should be used when collecting information on

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subjects' adverse events.AEs will be collected for all adverse events from the time the subject signs the
informed consent form until 28 days after the last dose or until the subject starts a new antineoplastic
therapy (safety follow-up period).The investigator must monitor the patient's health status for the
duration of the trial.AEs will be collected from the time of the signing of the informed consent form
until 28 days after the last dose or until the subject starts a new antineoplastic therapy (safety follow-
up period). Clinical adverse events occurring after signing the informed consent and prior to the first
dose are recorded in the CRF as history/concomitant disease and are not recorded as AEs unless one of
the following conditions is met:

Injury/damage resulting from any clinical laboratory test manipulation;

Adverse events resulting from discontinuation of medication associated with the
trial protocol;

Adverse events caused by medications other than the trial medication taken as part
of the treatment regimen.
AEs will no longer be actively collected at the end of the safety follow-up period; however,
investigators will still be required to report to the Collaborator (or Collaborator-appointed CRO) if
they become aware of an SAE that is reasonably causally related to the trial medicinal product.
Sources of AEs include:
Patient responses to questions about his/her health status (standardized non-leading
questions such as "How have you felt since your last visit?" asked at each visit). The patient's
self-reported symptoms.
The patient's self-reported symptoms.
Findings or tests that the investigator assesses as clinically significant changes or
abnormalities.
Other information relevant to the patient's health (e.g., hospitalization) that comes to
the researcher's attention.
8.1.5
Documentation of adverse events
The Investigator must document all adverse events on the Adverse Events form provided in each
patient's eCRF which should include the information below:
Name of adverse event
Date and time of initiation (time may be omitted if not applicable)

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Severity
Relationship to the test drug
Measures taken with respect to the test drug
Other measures taken
Date and time of regression (time may be omitted if not applicable)
Diversion
Whether serious adverse event and corresponding severity criteria
Name of the adverse event
The name of the adverse event should be in medical terminology and the medical diagnosis
should be used in preference to the medical diagnosis, or if the diagnosis cannot be clarified, separate
symptoms/signs should be recorded separately, and the diagnosis updated when the subsequent
diagnosis is clarified, replacing the previous symptoms/signs with the diagnosis . If the same adverse
event occurs more than once in a patient and the patient has recovered between adverse events, this
adverse event should be recorded separately according to the number of occurrences.
It is important to note: the measure taken is not the adverse event, the reason for the measure is
the adverse event. Hospitalization is not an adverse event; the cause of the hospitalization is an
adverse event. Death is not an adverse event, the cause of death is an adverse event (sudden
unexplained death can be recorded as "unexplained death").
Date and time of onset
The onset of an adverse event is the date when the first sign or symptom is first observed. If the
adverse event is an abnormal laboratory test or examination result of clinical significance, the start
time is the date of sampling or examination. In the case of progression from an adverse event to a
serious adverse event, the start of the date on which the adverse event is judged to have been upgraded
to a serious adverse event is taken as the time of the serious adverse event.
Measures taken on the test drug
Measures taken on a test drug product to address an adverse event must be categorized as one of
the following:
Permanent discontinuation-The trial medicinal product is permanently discontinued
because of a specific AE.

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Dose unchanged-The specific AE does not require a change in the dosing regimen of
the investigational medicinal product, which continues to be administered.
Dose reduction-Dose reduction because of the specific AE.
Suspension-Temporary
discontinuation
(suspension)
(including
subject-initiated
discontinuation) of the Test Drug because of a specific AE, followed by resumption of dosing.
Unknown-Used only when there is no certainty about the action taken.
Not applicable-Discontinuation of the Test Medicinal Product for reasons other than
the specified AE, e.g., the study was terminated, the subject died, the Test Medicinal Product
was discontinued before the AE occurred.
Other measures taken
Adverse events that require treatment to be given must be treated using recognized standards of
care to protect the health and interests of the patient. Appropriate CPR equipment and medications
must be available to ensure that the best possible treatment is provided in an emergency.
If medication is used to treat an adverse event, the medication used should be recorded in the
combined medication record.
End date and time
The end date of the AE needs to be completed in accordance with the requirements for
completion of the CRF and SAE report form.
Categorization
The attribution of an adverse event must be categorized as one of the following:
Recovery/Recovered: the "(serious) adverse event termination date" should be
indicated.
Improved/remitting: status recovering/improving or stabilized.
Not recovered/not cured/continuing: event in progress.
Recovered/recovered with sequelae: only if the subject will have sequelae that last for
a prolonged period of time or for life, e.g., blindness due to diabetes mellitus, hemiplegia due
to stroke. The "(Serious) Adverse Event Termination Date" should be indicated.
Death: when the adverse event is fatal the time of death needs to be recorded.
Unknown: The adverse event is not known to the investigator, e.g., subject lost to

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follow-up.
8.1.6
Follow-up of adverse events
After the initial AE report, the investigator is required to initiate follow-up with each subject and
provide further information to the collaborator regarding the subject's status. The frequency of follow-
up visits should be determined based on the severity of the adverse event, diagnostic and therapeutic
routines, and trial protocol requirements. If the adverse event is not completed at the current visit, it
should be asked and recorded again at the next visit; if there is a combination of medication, it should
be collected and recorded; if the patient is treated in the local hospital, the local hospital treatment
records and medication information should be collected as much as possible. Specific requirements
should be in accordance with the relevant SOPs of the healthcare organization.
AEs (regardless of causality) that have not fully recovered or stabilized at the end of the safety
follow-up period must be followed until recovery/cure (return to baseline level or cure) with or
without sequelae, clinical stability, reasonable explanation, death of the subject, or loss to follow-up.
8.2 Serious Adverse Events (SAE)
8.2.1
Definition of Serious Adverse Event
Serious Adverse Event (SAE) means an adverse medical event such as death, life-threatening,
permanent or severe disability or loss of function, subject requiring hospitalization or prolonged
hospitalization, and congenital anomalies or birth defects that occur after the subject has received the
test drug.
Table6 Definitions of Serious Adverse Events
SAE Definition
Guideline
Death
AE is the direct or primary cause of a subject's death.
Life-threatening
The occurrence of an adverse event that immediately poses a risk of death to the
subject. Excludes those adverse events that may result in death after serious
progression, e.g., drug-induced hepatitis without liver failure.
Permanent
or
Serious
Disability
or
Loss
of
Function
Any adverse event that results in an injury that impairs or destroys a subject's
function, physiology, or both, physical activity, or quality of life.
Subject
requires
hospitalization or prolonged
hospitalization
An event requiring extended treatment for an already hospitalized subject shall
be recorded as an SAE Examples of such events include transfer from routine hospital
care to an intensive care unit (ICU) or if the event results in an extension of an
existing planned hospital stay.
The following hospitalizations should not be considered SAEs:
Retention in the emergency department or other hospital unit for no more
than 24 hours that does not result in hospitalization (unless considered a
medically significant event or life-threatening);
Elective surgery that was planned prior to signing the informed consent
form;
Hospitalization required for routine health screening (e.g., routine
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Hospitalizations that are not for the purpose of disease treatment and are
planned prior to enrollment and need to be documented;
Admissions that are not related to a health condition and do not require
medical/surgical intervention (e.g., family reasons, etc.).
Adverse
medical
events
such
as
congenital
anomalies or birth defects
The presence of congenital anomalies, malformations, etc. in the offspring of the
subject.
Other
significant
medical events
Medical and scientific judgment must be used to determine whether to expedite
reporting of other conditions, such as important medical events that may not be
immediately life-threatening, fatal, or hospitalizing, but are also generally considered
serious if medical measures are needed to prevent one of the above conditions from
occurring. Examples include critical treatment in the emergency room or allergic
bronchospasm at home, malaise or convulsions without hospitalization, development
of drug dependence or addiction, etc.
8.2.2
Reporting of Serious Adverse Events
Any serious adverse event that occurs during the trial, regardless of whether it is related to the
trial drug or not, the investigator should provide prompt rescue treatment and report it to the partner
(or CRO appointed by the partner) by completing, signing, and dating the "Serious Adverse Event
(SAE) Report Form" provided by the partner, within 24 hours of notification. The investigator should
provide other required information, such as autopsy report and final medical report, to the collaborator
and the Ethics Committee. In particular, if the SAE is fatal or life-threatening, the Collaborators must
be informed immediately, regardless of the amount of AE information available. This timeframe also
applies to additional new information from previous SAE reports (follow-up visits), as well as initial
and follow-up reports for pregnancy exposures. In rare instances where the investigator is not
immediately aware of the occurrence of an SAE (e.g., if an outpatient study patient initially seeks
treatment elsewhere), the investigator should report the event within 24 hours of learning of the event
and document the time when he or she first became aware of the SAE.
Investigators must provide their assessment of causation when reporting serious adverse events.
If the Investigator's assessment of causation is missing or unavailable, the Collaborator or
Collaborator-appointed CRO shall immediately contact the Investigator and send an Urgent Medical
Challenge requesting that assessment; if the Investigator is temporarily unable to provide an
assessment of causation, it will be left to the judgment of the Collaborator until such time as the
Investigator's assessment can eventually be obtained.
If the investigator is unable to determine whether the adverse event is a Serious Adverse Event, it
will be considered a Serious Adverse Event until its nature can be demonstrated.
The investigator should sign and read the relevant safety information of the clinical trial provided
by the collaborator in a timely manner after receiving it and consider the treatment of the subjects,
whether to adjust it accordingly, and communicate with the subjects as early as possible if necessary,

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and should report the suspected and unintended serious adverse events provided by the collaborator to
the Ethics Committee.
8.2.3
Follow-up of Serious Adverse Events
The follow-up requirements of SAE are the same as those of AE, and the investigator should fill
in the Serious Adverse Event (SAE) Report Form in a timely manner and report it to the collaborator
and the CRO assigned by the collaborator in accordance with the SAE reporting process.
8.3 Suspected Unexpected Serious Adverse Reactions
8.3.1
Definition of Suspected Unanticipated Serious Adverse Reaction
Suspected Unexpected Serious Adverse Reaction (SUSAR) refers to a suspected and
unanticipated serious adverse reaction whose clinical manifestations are of a nature and severity that
exceeds the information already available in the investigator's manual of the study drug, the
specification of the marketed drug, or the summary of product characteristics. Unintended Adverse
Reaction means an Adverse Reaction whose nature, severity, consequences, or frequency are different
from the expected risk described in current information about the test drug (e.g., documents such as
the Investigator's Manual). The investigator's brochure serves as the primary document that provides
the safety reference information used to determine whether an adverse reaction is anticipated or
unanticipated. For example, (1) acute renal failure is listed as an adverse reaction in the investigator's
brochure, but the development of interstitial nephritis during the course of the trial should be judged as
an unintended adverse reaction, and (2) hepatitis is listed as an adverse reaction in the investigator's
brochure, but the development of acute severe hepatitis during the course of the trial should be judged
as an unintended adverse reaction.
8.3.2
Reporting of Suspected Unintended Serious Adverse Reactions
Any safety-related information received by the Collaborator from any source should be analyzed
and evaluated immediately, including severity, relevance to the test drug, and whether it is an expected
event. The Collaborator shall make a SUSAR Rapid Report to all investigators participating in the
clinical trial, the clinical trial site, the ethics committee, and the drug regulatory and health authorities.
（1）Start/end time of the rapid report: the start time is the date of approval of the clinical
trial/start date of the implied license of the national drug review agency, and the end date is the end
date of the follow-up of the last case of subjects in China (unanticipated serious adverse reactions
occurring after the end of the follow-up of the clinical trial and before obtaining the conclusion of the
review and approval should also be reported rapidly).

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（2）Duration of the rapid report

Fatal or life-threatening SUSAR: first report within 7 days, and report and improve
follow-up information within the following 8 days.

Non-fatal or life-threatening SUSAR: first report within 15 days.

Day 0 is the day the partner is first notified of a signed version of a valid report.
8.3.3
Follow-up for Rapid Reports
After the initial report (SUSAR), the collaborator should continue to follow up on serious
adverse reactions and report relevant new information or changes to the previous report, etc., in a
timely manner in the form of a follow-up report, with a reporting timeframe of 15 days from the date
of obtaining the new information;
8.4 Reporting of other potential serious safety risk information
（1）Other potentially serious safety risk information should also be reported to the national
drug review organization by the partner as soon as possible, while medical and scientific judgments
need to be made in each case.
（2）In general, this is the case for information that clearly affects the assessment of the risk-
benefit of a drug product or information that may contemplate a change in drug usage or affect the
overall drug development process.
I. For known, serious adverse reactions with an increased incidence judged to be clinically
important;
II. For obvious hazards to exposed populations, such as ineffectiveness of the drug in the
treatment of life-threatening diseases;
III. significant safety findings (e.g. carcinogenicity) in newly completed animal tests.
IV. The latest global safety alerts for similar drugs or the latest safety concerns disclosed in
newly completed epidemiologic investigations or academic conference papers.
8.5 Adverse Events of Special Concern
An Adverse Event of Special Concern is an event for which close monitoring is particularly
warranted to enhance the understanding of the safety of the trial drug. Adverse events of special
concern were reported by the investigator to the collaborator within 24 hours. Adverse events of
special concern for this study include:

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8.5.1
Cytokine release syndrome (CRS)
Oncolytic virus therapy may result in the release of inflammatory factors into the bloodstream,
resulting in the formation of cytokine syndrome, which usually peaks 5-7 days after infusion. Severe
CRS may result in acute respiratory distress syndrome, multi-organ failure, or even life-threatening.
Once serious cytokine release syndrome is suspected or considered, it is recommended that the clinic
should intensively test body temperature, blood pressure, oxygen saturation and neurological
examination, and should draw blood for cytokine testing in a timely manner. The initial symptoms of
cytokine syndrome are often nonspecific and may manifest as nonspecific symptoms in all major
systems of the body, including respiratory, gastrointestinal, cardiovascular, renal, and neurologic.
CRS will be graded according to the American Society for Transplantation and Cellular Therapy
(ASTCT) Consensus for Grading Immune Effector Cell-Related CRS and Neurotoxicity.
Table7 ASTCT CRS Grading Consensus
CRS parameters
Grade 1
Grade 2
Grade 3
Grade 4
Fevera
Body temperature
≥38°C
Body temperature
≥38°C
Body
temperature
≥38°C
Body
temperature
≥38°C
Combined
Hypotension
No
No need for
antihypertensive
medication
Need for one
antihypertensive
medication with or
without vasopressin
Need for multiple
antihypertensive
medications
(excluding
vasopressin)
Combined (or) b
Hypoxia
None
Needs low oxygen
flow nasal
cannulacor oxygen
blowing therapy
Requires high
oxygen flow nasal
cannulac, face mask,
non-rebreathing
mask, or venturi
mask oxygen therapy
Need for positive
pressure
ventilation (e.g.,
CPAP, BiPAP,
tracheal
intubation
mechanical
ventilation)
Reference: ASTCT CRS grading consensus
Organ toxicity leading to CRS may be graded according to CTCAE v5.0 without affecting CRS grading.
aFever is defined as a temperature ≥38°C that cannot be reasonably explained by any other cause. For subjects who
develop CRS and receive antipyretic or anticytokine therapy (e.g., tolizumab or steroids), fever need not be
considered when grading the severity of subsequent CRS. In such cases, CRS is graded based on hypotension and/or
hypoxia.
bCRS grading is based on a more severe event (e.g., hypotension or hypoxia) that cannot be reasonably explained by
any other cause. For example, a subject with a temperature of 39.5°C, hypotension requiring treatment with 1
antihypertensive medication, and hypoxia requiring treatment with a low oxygen flow nasal cannula would be
classified as having a CRS of grade 3.
cA low oxygen flow nasal catheter was defined as an oxygen delivery rate of ≤6 L/min. low oxygen flow also
included blown oxygen delivery, sometimes used in pediatric subjects. (d) High oxygen flow nasal cannulae are
defined as oxygen delivery at a rate of >6 L/min.

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If a subject develops any of the above symptoms, the investigator should immediately perform
cytokine testing (including but not limited to IL1a, IL2, IL6, TNF-α, and IFN-γ). If a subject develops
persistent mild CRS or moderately severe CRS, tolizumab (monoclonal antibody to IL-6) and/or
corticosteroids should be promptly administered, along with appropriate supportive therapeutic
measures such as oxygen, antipyretic and analgesic agents, and antihypertensive medications.
Table8 Generalized Management of CRS*
1.
For the first presentation of fever, a thorough evaluation should be performed immediately and the infection
should be treated empirically with broad-spectrum antibiotics. There should be no unwarranted assumption that
fever is caused by CRS.
2.
Currently, prophylactic tolizumab is not required except in clinical trials.
3.
Repeated IV fluid pushes should be avoided whenever possible, as this may exacerbate the complication of
capillary leakage.
4.
In subjects who develop recurrent or refractory hypotension associated with CRS, tolizumab should usually be
used and should be administered before CRS reaches grade 3 or worse.
5.
Tolizumab is the only drug approved by the FDA for the treatment of CRS and is the first-line treatment for
CRS.
6.
Multiple doses of tolizumab may be needed, but usually no more than 2 doses should be given without the
addition of corticosteroids.
7.
Tolizumab reduces the severity of CRS and does not interfere with the efficacy of immunotherapy.
8.
If there is no response to tolizumab, corticosteroids should be added. Corticosteroids may also be given at the
same time as the first dose of tolizumab.
IV = intravenous
*The items in the table above are suggested measures or generic considerations or points. The investigator should
prescribe medications and take appropriate measures for the subject based on medical judgment, considering the
subject's medical care and safety. The investigator should also review the complete prescribing information for all
medications (e.g., tolizumab) that have been prescribed.
8.5.2
Tumor Lysis Syndrome (TLS)
Tumor lysis syndrome (TLS) is a group of clinical syndromes characterized by hyperuricemia,
hyperkalemia, hyperphosphatemia, hypokalemia, and acute renal failure caused by the release of
potassium, phosphate, and uric acid into the blood circulation during the administration of a test drug,
which can occur rapidly due to the rapid destruction and lysis of a large number of tumor cells under
the action of the drug or spontaneously, and is a potentially serious complication of the early induction
of treatment for malignant tumors. TLS occurs most often in patients with tumors associated with high
proliferation rate, high tumor load, and high drug sensitivity. The clinical manifestations of TLS
depend on the severity of metabolic abnormalities, and mainly include nausea, vomiting, shortness of
breath, congestive heart failure, cardiac arrhythmia, cloudy urine, edema, and muscle spasms. The
severity of TLS is differentiated according to renal function, cardiac arrhythmias, seizures, etc.
Patients with TLS may be treated with hydration, diuresis (preferred to labeled diuretics such as
furosemide, etanercept, bumetanide), alkalinization of the urine (bicarbonate is not recommended),
lowering of the uric acid (labrynthase is recommended) and correction of electrolyte disturbances.

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Table9 TLS grading system
Grade I
Grade II
Grade III
Grade IV
Impaired renal
function
SCr 1.5mg/dl or
CCr30~45 mL/min
SCr 1.5~3.0 mg/dl
or CCr
10~30mL/min
SCr 3.0~6.0 mg/dl
or CCr
10~20mL/min
SCr>6.0 mg/dl or
CCr<10 mL/min
Nature of
arrhythmia
No indication for
intervention
No indication for
urgent intervention
Symptomatic,
incompletely
controlled, or
manageable with a
device
Life-threatening,
e.g., arrhythmia with
congestive heart
failure, hypotension,
syncope, shock
Seizures
None
A brief generalized
seizure that is well
controlled by
medication or an
occasional focal
motor seizure that
does not interfere
with daily life.
Seizures with
altered
consciousness;
poorly controlled
epilepsy, generalized
explosive seizures
despite drug
intervention
Prolonged,
recurrent, difficult-
to-control epilepsy
(e.g., status
epilepticus and
intractable
epilepsy).
Note: SCr: serum creatinine, CCr: endogenous creatinine clearance.
Table10 Recommendations for management of electrolyte disorders
Electrolyte abnormalities
Recommendations for management of electrolyte
abnormalities
Hyperphosphatemia
Moderate (≥2.1 mmol/L)
Avoid phosphorus-containing drugs intravenously,
aluminum hydroxide (50~150 mg/kg/d) 1ci/6h, use
1~2d
Severe
Dialysis (HD, PD) CAVH, CVVH, CAVHD, CVVHD
Hypocalcemia (≤1.75 mmol/L)
Asymptomatic
No treatment required
Accompanying symptoms
Calcium gluconate under cardiac monitoring
50~100mg/kg slow IV push
Hyperkalemia
Moderate (≥6.0 mmol/L) and asymptomatic
Avoid intravenous or oral potassium supplementation,
give ECG and cardiac rhythm monitoring.
Severe (>7.0 mmol/L) with or without symptoms.
In addition to the above: calcium gluconate 100-200
mg/kg IV and regular insulin (0.1 U/kg) + D25 2 mg/kg
IV and 5% sodium bicarbonate 2-4 mL/kg IV for
arrhythmias; dialysis.
Acute renal insufficiency
Fluid and electrolyte balance therapy Uric acid and
phosphate therapy Adjustment of renal drug
metabolism dose Dialysis or hemofiltration
Note: HD: hemodialysis, PD: peritoneal dialysis CAVH: continuous arterial-venous hemofiltration, CVVH:
continuous venous-venous hemofiltration, CAVHD: continuous arterial-venous hemodialysis, CVVHD: continuous
venous-venous hemodialysis, D25: diclofenac sulfide
8.5.3
Adverse events related to intratumoral injection
During the intratumoral injection administration of the test drug to the subjects, depending on the
location of the tumor, some risks may occur during the puncture process: for example, the needle may
puncture the lung tissue and the pleura of the dirty layer during the administration of the drug to the

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thoracic malignant tumors to form a pneumothorax; gastrointestinal malignant tumors: it may puncture
the wall of the stomach or the wall of the intestines to cause a gastrointestinal perforation; or it may
puncture blood vessels and lead to hemorrhage during the injection of the test drug to the tumor, and
so on.
Therefore, when lysosomal virus is administered, it should be performed under endoscopic, CT
or ultrasound guidance to avoid the above events. If pneumothorax or gastrointestinal perforation
occurs during drug administration, the clinical condition of the subject should be closely observed and
timely and appropriate treatment measures should be taken:
Pneumothorax: Untimely or inappropriate treatment of persistent pneumothorax will affect the
subject's cardiopulmonary function, causing serious damage to circulatory and respiratory functions,
and may even threaten life, requiring early and aggressive treatment. The diagnosis can be confirmed
by clinical symptoms, signs and imaging. Typical symptoms are sudden chest pain, followed by chest
tightness and dyspnea, and irritating cough. Pneumothorax subjects should have absolute bed rest and
adequate oxygen intake to minimize lung activity, which is conducive to gas absorption and lung
reexpansion. Consultation with relevant departments should be requested in time, and operations such
as pleural cavity puncture and aspiration or closed chest drainage should be performed to promote the
early reexpansion of lung tissues. Surgery can be performed if drainage fails or if necessary.
Gastrointestinal perforation: The seriousness of perforation is that a large amount of
gastrointestinal fluid flows into the abdominal cavity after perforation, causing chemical or bacterial
peritonitis and toxic shock. Clinical manifestations: acute abdominal pain, severe cutting or burning
persistent pain, may be accompanied by fever, nausea and vomiting, and in severe cases, infectious
shock may occur. Significant signs of peritoneal irritation can be seen on examination, manifested by
abdominal pressure, rebound pain and muscle tension, and abdominal refusal to be pressed. The
diagnosis is confirmed by clinical symptoms, physical signs and X-ray/CT examination. Treatment of
GI perforation begins with terminating the continued leakage of gastrointestinal contents into the
abdominal cavity and allowing the acute peritonitis to resolve. Conventional conservative treatment
includes water fasting, placement of a nasogastric tube to suction the gastric contents for continuous
gastrointestinal decompression, application of proton pump inhibitors to reduce digestive fluid
secretion, nutritional support and correction of electrolyte disorders, and systemic anti-infective
treatment with antibacterial agents. If the symptoms are not relieved or worsened after conservative
treatment, emergency surgery is needed.
If the syringe punctures a blood vessel during the operation and causes internal bleeding, the

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operation should be suspended in time, and the clinical manifestations and vital signs of the subject
should be closely observed. Symptomatic treatment should be carried out according to the actual
situation in serious cases: including the application of hemostatic drugs, intravenous rehydration, and
intravenous blood transfusion treatment can be given when there is massive bleeding with progressive
decrease of hemoglobin and obvious anemia symptoms.
If VSV-02 is inadvertently injected into a vein and enters the systemic circulation, acute toxicity
or anaphylaxis may occur. Anaphylactic reactions during administration may be characterized by chills,
fever (usually around 38 ° C in mild cases and 40 ° C or more in severe cases), and may be
accompanied by headache, nausea, vomiting, rash, itching, urticaria, tachypnoea, general malaise,
arthralgia, hypotension, hypertension, bronchospasm, or other anaphylactic reactions. In severe cases,
angioneurotic edema, laryngospasm, asthma, anaphylaxis, heart failure, and pulmonary edema may
occur. Allergic reactions usually occur rapidly and may be life-threatening in severe cases. Some
subjects may experience delayed hypersensitivity reactions, mostly within 1 week after administration,
which may be characterized by local or generalized itching and rash.
Clinical manifestations and vital signs will be closely monitored during administration. If
anaphylaxis occurs, the investigational product will be immediately discontinued and symptomatic
treatment will be initiated. Symptomatic treatment may include antihistamines and/or glucocorticoids.
8.6 Pregnancy.
Male and female subjects of childbearing potential must agree to use effective, medically
approved contraception from the time of first dose until 6 months after discontinuation. The
investigator should emphasize the time frame requirement for the use of contraception to the
investigator at the time of the subject's informed consent and advise the subject of the possible effects
of the application of the test drug on the fetus.
Female subjects should discontinue the study drug and notify the investigator as soon as they
become pregnant during study treatment. Female subjects must withdraw from the study. The
investigator should complete the Pregnancy Report Form within the same timeframe as the Serious
Adverse Event Report and report it to the Collaborator and the Collaborator-appointed CRO within 24
hours and follow the pregnancy outcome (e.g., termination of pregnancy, labor and delivery) until the
end of the pregnancy/third trimester of the newborn. Male subjects should also notify the investigator
immediately if their heterosexual partner becomes pregnant during treatment. The investigator will
obtain a separate informed consent form from their female partner for the collection of pregnancy-
related information and follow up with their heterosexual partner until three months after the end of

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pregnancy/delivery.
Pregnancy is not an SAE, but abnormal pregnancy outcomes (spontaneous abortion, medically
selected abortion, fetal/neonatal congenital anomalies, malformations, or deaths, etc.) will need to be
documented and reported as an SAE at the same time as the pregnancy report is completed. Subjects
should be appropriately monitored and cared for until the end of the pregnancy.
8.7 VSV-02 Exposure Report
VSV-02 is a herpetic stomatitis virus that may cause infection in subjects. VSV-02 should not be
given to subjects who have significant immune disorders in addition to the underlying cancer or who
are receiving prohibited immunosuppressive medications.Due to the potential for transmission of
VSV-02 and vesicular stomatitis virus as a result of unintentional exposures, healthcare workers, close
contacts (family members, caregivers, sexual or bed partners), pregnant women, and newborns should
avoid contact with injected lesions of subjects receiving treatment, dressings or body fluids.
Caregivers should wear protective gloves when assisting subjects in applying or changing occlusive
dressings and follow safety precautions for handling used dressings, gloves, and cleaning materials. If
accidental exposure to VSV-02 occurs during preparation or administration, the exposed area should
be rinsed with water for at least 15 minutes. If broken skin or needle punctures come into contact with
VSV-02, the affected area should be thoroughly cleaned with soap and water and/or disinfectant.
If a family member, caregiver, or healthcare worker in close contact with the subject is suspected
of being exposed to VSV-02 during the subject's treatment with VSV-02, report the exposure event to
the Collaborator as specified below. In addition to reporting unanticipated exposure events during
study treatment, investigators should monitor potential exposure events that occur within 28 (±7) days
of the last dose of VSV-02.
For any potential or known unintended exposure, the investigator should report the exposure
event to the Collaborator within 24 hours of being informed of the exposure event. If necessary, the
Collaborator will attempt to follow up with the Exposed Individual to gather additional information
about the Exposed Individual's contact with clinical trial subjects, signs and/or symptoms associated
with the exposure, medical history, and/or exposure outcomes. If an exposed individual reports signs
or symptoms suspected to be related to VSV-02 exposure, a swab may be taken from the exposed
individual within 3 days of the onset of symptoms or signs to confirm the presence of VSV-02 in the
lesion.
9
Statistical Considerations
Detailed summary and statistical analysis methods for the data collected for this study will be

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included in a Statistical Analysis Plan (SAP), which will be developed after the protocol and CRF are
finalized and finalized prior to database locking and data unblinding.The SAP will specify and
describe in detail all elements of the planned statistical analyses based on the key features of the
protocol.
9.1 Sample size estimation
This study is expected to enroll 3 to 6 subjects.
9.2 Analytic Population
Full Analysis Set (FAS)
The Full Analysis Set (FAS) will include all enrolled subjects who have used the trial
drug at least once. The FAS will be used for demographic data, baseline descriptive
analysis, medication adherence, trial coadministration, and efficacy analysis.
Efficacy Evaluable Set
(EEAS)
A subset of the FAS that includes subjects with at least one post-treatment tumor
assessment. The EEAS will be used for efficacy analysis.
Safety Set (SS)
Includes all subjects who have received at least one dose of the investigational drug; SS
will be used for safety and tolerability analyses.
Biodistribution Analysis
Set
This analysis set will include all enrolled subjects who have received at least one dose of
the test drug and have completed at least one post-dose biodistribution blood collection.
This analysis set will be used to assess biodistribution.
Stool Assessable
Analysis Set
This analysis set will include enrolled subjects who have received at least one trial drug
and completed at least one fecal swab collection. This analysis set will be used to assess
the level of VSV-02 Injection gDNA and active virus detected in fecal samples.
Urine Assessable
Analysis Set
This analysis set will include enrolled subjects who have received at least one trial drug
and have completed at least one urine swab collection during the treatment period. This
analysis set will be used to assess the level of VSV-02 Injection gDNA and active virus
detected in urine swab samples during the Treatment Period.
Saliva Assessable
Analysis Set
This analysis set will include enrolled subjects who have received at least one trial drug
and have completed at least one saliva swab collection during the treatment period. This
analysis set will be used to assess the level of VSV-02 injectable gDNA and active virus
detected in saliva swab samples during the treatment period.
Injection Site
Assessable Analysis Set
This analysis set will include enrolled subjects who have received at least one trial drug
and have completed at least one injection site swab collection. This analysis set will be
used to assess the levels of VSV-02 Injection gDNA and active virus detected on the
surface of the injection site.
Pharmacodynamic
Analysis Set
This analysis set will enroll subjects who have received at least one trial drug and have at
least one assessable biomarker or cytokine parameter. This analysis set will be used to
assess biomarker and cytokine levels of VSV-02 Injection.
Immunogenicity
Analysis Set
This analysis set will include all subjects who have received at least one trial drug and
have data from at least one post-baseline immunogenicity sample. This analysis set will
be used to assess the immunogenicity of VSV-02 Injection.
9.3 Statistical Analysis
9.3.1
General Methods
Measurement information is statistically described by the number of cases, mean, standard
deviation, median, maximum and minimum values. Count or grade information is described
statistically by the number of cases and percentages. Survival data will be presented at the 25th, 50th
(median), and 75th percentile if estimation is possible. In addition, the number and percentage of
subjects with events and censored subjects will be presented. A list of individual subject data will be

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provided to support the provision of summary tables. If there are any deviations in the actual statistical
methods used from those provided in the study protocol, these will be described and justified in the
SAP. All statistical analyses will be performed using Statistical Analysis Software (SAS®) version 9.4
or later.
9.3.2
Distribution of subjects
The number and percentage of subject cases in each analyzed population will be summarized,
and in addition, the primary reasons for discontinuation of VSV-02 will be summarized.
9.3.3
Demographic and Baseline Characteristics
Baseline characteristics and demographic data for FAS will be summarized.
9.3.4
Safety Analysis
Safety analyses will be performed based on the Safety Analysis Set.
9.3.5
Validity Analysis
Efficacy analysis will be based on FAS and EEAS.This study will initially evaluate the
antitumor activity of VSV-02. Efficacy endpoints, including ORR and DCR, will be evaluated using
RECIST version 1.1 and iRECIST.
ORR is defined as the percentage of subjects achieving CR or PR for overall remission and DCR
is defined as the percentage of subjects achieving CR, PR or SD. ORR and DCR will be presented by
dose level at each program plan time point. 95% CIs for ORR and DCR will be calculated using the
Clopper-Pearson method.
In addition, other efficacy parameters such as DoR, PFS and OS will be evaluated.
For the subset of subjects who experience remission, DoR (defined as the time from the date of
the first documented remission [CR or PR] to disease progression or death from any cause [whichever
is earlier]) will be summarized using Kaplan-Meier curves. For subjects who experienced remission
during the study period but did not subsequently experience disease progression or death or were lost
to follow-up, the DoR will be censored at the date of the final tumor assessment.
PFS, defined as the time from the date of first administration of study drug to disease
progression or death from any cause (whichever is earlier), will be summarized using Kaplan-Meier
curves. For subjects who do not progress or die or are lost to follow-up during the study period, PFS
will be censored at the date of the final tumor assessment.
OS is defined as the time from first study treatment to the date of death due to any cause, and

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will be censored at the date of last contact obtained for subjects who have not experienced death or
loss to visit as of the time of study analysis.
Kaplan-Meier estimates of median DOR, PFS and OS, first and third quartiles will be presented
by dose level at study entry, and 95% CIs will also be calculated for subjects who progressed or died if
a sufficient number of subjects progressed or died.Survival and 95% CIs will be calculated at each
time point.The Greenwood formula will be used to calculate Kaplan-Meier curve standard error of the
estimates. In addition, Kaplan-Meier plots of DOR, PFS, and OS will be plotted by dose level at the
time of study enrollment.
9.3.6
Biodistribution and viral shedding analysis
The biodistribution of VSV-02 will be evaluated by detecting the viral gDNA level in blood
samples using real-time quantitative polymerase chain reaction (qPCR) method. Viral shedding will be
evaluated by detecting viral gDNA levels in urine, feces, nasopharyngeal fluid and injection site swabs.
Biodistribution and viral shedding analyses will be based on the biodistribution analysis set and
associated viral shedding analysis set defined in Section9.2 . The proportion of subjects meeting the
criteria for detectable DNA at each time point will be calculated. Summary statistics will be presented
by dose level.
9.3.7
Immunogenicity Assessment
All available immunogenicity data at each VSV-02 concentration level will be presented by dose
level and immunogenicity status.
9.3.8
Biomarkers and Cytokines Assessment
Biomarkers and cytokines and their changes relative to baseline are statistically characterized
according to their profile. Exploratory analyses of the parameters were performed as needed.
10
Data Processing and Record Keeping
10.1
Data collection and management responsibilities
Prior to clinical trial data management, a Data Management Plan (DMP) is developed by the data
management department based on the actual situation of the project. The DMP is a dynamic document
written by the data management personnel based on the clinical trial protocol, which specifies and
records in detail and comprehensively the data management tasks for a particular clinical trial,
including personnel roles, work content, operation specifications, etc.
10.2
Data Collection and Methods

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In this trial, the Electronic Data Capture System , EDC, was used for data collection, and data
administrators/database programmers created accounts and granted different privileges to access the
EDC system according to different identities.
The data recorded in the Electronic Case Report Form (eCRF) should come from the source files
and be guaranteed to be consistent with the source data. All source documents should be kept clear
and neat to ensure that the data can be accurately identified. Permanent copies of study visit records
will be considered source documents for recording enrolled subject data. Data from source documents
such as study medical records should be entered into the eCRF by the entry personnel in a timely and
accurate manner.
10.3
Data Cleaning and Challenge Resolution
Data cleansing involves the process of data verification (system logic checking and manual logic
checking), triggering of queries, investigator/research assistant answering of queries, data updating,
until the queries are resolved.
Data cleanup is regularly performed by data managers and supervisors through the EDC system,
and medical supervisors regularly perform medical audit work through the EDC system. For EDC
queries, investigators/research assistants were online to give answers and/or correct erroneous data.
The query initiator confirms the answered data and can repeat the query if necessary.
10.4
Correction and review of data
Data can be modified by the data entry staff or by the investigator after verification of the data,
and the reason for the modification must be filled out on eCRF. The researcher has the authority to
review all final data.
10.5
Data Lock and Export
The data administrator locks the data after all the data have been reviewed and approved. Any
modification of data after locking must be signed by the collaborator, researcher, statistician, medical
personnel, data management personnel, etc. before execution. All data were finally exported from the
EDC database by the data manager and handed over to the statistician for analysis.
At the end of the study, the eCRF is printed and archived as needed. The Data Management
Center will maintain the eCRF.
Data management related tasks not exhaustively specified in the protocol are performed with
reference to the data management plan for this trial.

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10.6
Study Record Keeping
In order to ensure the evaluation and supervision by the State Drug Administration and the
sponsor, the investigator should keep all the study data according to the GCP, including all the subject
source data record information, such as study charts or original transcripts, signed informed consent,
and detailed records of drug distribution. After the completion of the trial, the PDF version of the
eCRF of all subjects in each study center shall be saved on CD-ROM to the corresponding study
center. The study data should be kept at least until 5 years after the termination of the clinical trial or 5
years after the approval of the test drug to be marketed, and the destruction of any data is not allowed
without the written consent of the sponsor.
The ownership of all the data of this clinical study belongs to the sponsor, and the investigator is
not allowed to provide them to a third party in any form without the written consent of the sponsor,
except for the requirement of the State Drug Administration.
10.7
Study Publication and Data Sharing Policy
Information provided to the investigator by the sponsor (including this clinical trial protocol) is
non-public information and must be kept confidential.
The research organization shall obtain written consent from the funder to communicate the
results of this clinical study at academic conferences or in journals. The publication of articles in
academic journals by the Research Organization shall be made after the Grantor has filed the relevant
patent application and shall be made with the written consent of the Grantor.
All published papers of this clinical research/clinical trial program will be signed by the principal
investigator as the first corresponding author (listed last among the co-corresponding authors and
showing his/her email address), and the ranking of the other authors will be determined by agreement
between the research institution and the funder. Page charges were borne by the first corresponding
author.
11
Code of Ethics and Informed Consent
11.1
Ethical norms
This trial was conducted in accordance with GCP, the Declaration of Helsinki, relevant
regulations and ethics committee review. The investigator should ensure that this trial is reviewed and
approved by a qualified ethics committee that meets the requirements of GCP. At the time of review,
the sponsor and the investigator should provide the ethics committee with the trial protocol, the
informed consent form, and other required materials. The sponsor can only supply the trial drug after

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receiving the approval from the ethics committee. The ethics committee must also be informed of
subsequent protocol additions and serious adverse events that may affect the safety and continued
participation of subjects in the trial. It is the responsibility of the investigator to report to the ethics
committee on the progress of the trial. When reviewing and approving the trial protocol, the Ethics
Committee must confirm the title of the protocol, the protocol number, and indicate the reviewed
protocol document and the date of review. During the trial, if there are any new amendments to the
trial protocol, informed consent, etc., the written approval of the relevant regulatory unit should be
obtained again in accordance with the regulations.
11.2
Informed Consent
Subjects must give informed consent for participation in this trial prior to receiving treatment in
this trial in order to protect the legal rights of the subjects. It is the responsibility of the investigator to
provide the subject or his/her designated agent with a complete and comprehensive description of the
purpose of the study, the manner in which the study will be conducted, the action of the drug, the
reasonably expected benefits, the possible toxicities and side-effects, and the possible risks. Subjects
shall be made aware of their rights, the risks to be borne and the benefits, and shall be informed in a
timely manner of any new information regarding the drug to be used in the trial. Subjects should be
informed that the clinical trial is conducted on a voluntary basis, that they may withdraw
unconditionally from the trial at any time during the trial, and that they will not be penalized for
withdrawing from the trial. Subjects should be informed that the investigator and sponsor have the
right to read, save and statistically process the subject's trial data in accordance with the provisions of
relevant regulations. The informed consent form should indicate the version and date of development
or revision. The informed consent form must be signed and dated by the subject (and the subject's
legal guardian), and the investigator performing the informed consent process must also sign and date
the informed consent form, which may also be signed by an independent witness who can attest to the
subject's consent to participate in the trial. One copy of the informed consent form should be retained
by the investigator and one by the subject. If significant new information regarding the trial drug is
discovered, the informed consent form must be revised in writing and sent to the Ethics Committee for
approval before consent is obtained from the subject again.
11.3
Confidentiality and privacy
The confidentiality and privacy of the subjects were kept strictly confidential by the participating
investigators, their staff, and the collaborators and their interventions. This confidentiality will extend
to tests covering biological sample testing and genetic testing in addition to clinical information

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related to subjects. Therefore, study protocols, documents, data and all other information generated in
the study will be kept strictly confidential. No relevant study information or data will be released to
unauthorized third parties without the written permission of the sponsor.
All research activities will be conducted in a private setting whenever possible.
The Study Monitor, other authorized representatives of the Collaborator, representatives of the
Ethics Review Board (IRB), regulatory agencies, or representatives of the pharmaceutical company
providing the investigational product may inspect all documents and records required to be maintained
by the Investigator, including, but not limited to, the medical records (office, clinic, or hospital) and
pharmacy records of the subjects in this study. The Clinical Research Center should allow access to
these records.
Subject contact information will be securely stored at each clinical research center for internal
use during the study. At the end of the study, all records will continue to be kept in a secure location
for longer than the period of time required by IRB review, institutional regulations, or partner
requirements.
12
Quality Assurance and Quality Control
All parties to the clinical trial such as collaborators, research centers and CROs shall take
appropriate quality control measures to ensure that the clinical trial complies with the requirements of
the Declaration of Helsinki, GCP, and appropriate laws, regulations and SOPs.
12.1 Requirements for Collaborators
（1）Collaborators or their representatives must provide the most current version of the
Investigator's Brochure (IB) for each unregistered clinical trial compound. For marketed products,
provide the IB and/or the most current product information.
（2）The Partner or its representative develops the final version of the clinical trial protocol
with the investigator and statistical expert. After all parties have reached an agreement, the clinical
trial protocol is signed and submitted to the Ethics Committee.
（3）The partner or its representative provides all investigators with a sufficient number of case
report forms and instructs the investigators to complete and keep them.
（4）The partner or its representative provides all investigators with sufficient trial materials to
support and allow the investigator to conduct the trial according to the defined protocol.
（5）The Partner or its representative reserves the right to terminate the clinical trial
prematurely due to recurring protocol violations, or other well-founded ethical concerns. If this is the

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case, both parties will review and consult with each other and take necessary measures to ensure the
rights of patients.
12.2
Duties of the Monitor Appointed by the Partner or its Representative
The clinical trial monitor is the primary contact between the collaborator and the investigator.
The monitor must follow GCP and SOP, visit the research center regularly or according to the actual
situation to carry out clinical monitoring, supervise the conduct and progress of the clinical trial, check
and confirm that all data records and reports, eCRF input are correct and complete, and consistent with
the original data, to ensure that the clinical trial is carried out in accordance with the clinical trial
protocol, and that the investigator should actively cooperate with the work of the monitor. The specific
content of the monitor includes:
（1）Confirming before the trial that the trial undertaking unit has appropriate conditions,
including staffing and training, laboratory equipment is complete and in good working order, with a
variety of test-related inspection conditions, estimated to have a sufficient number of subjects, and the
participating trial personnel are familiar with the requirements in the trial protocol.
（2）Monitor the investigator's implementation of the trial protocol during the trial, confirm that
informed consent has been obtained from all subjects prior to the trial, understand the enrollment rate
of subjects and the progress of the trial, and confirm that the enrolled subjects are qualified.
（3）Confirmed that all data were recorded and reported correctly and completely, and that all
case report forms were entered correctly and agreed with the original data. All errors or omissions
were corrected or noted, signed and dated by the investigator. Dose changes, therapeutic alterations,
comorbidities, intercurrent illnesses, missed visits, and missed tests should be recognized and
documented for each subject.
（4）Confirm that all adverse events are documented and that serious adverse events are
reported and documented within the required time frame; verify that the test drug is supplied, stored,
dispensed, and withdrawn in accordance with the relevant regulations and documented accordingly.
（5）Assist the investigator to carry out the necessary notification and application matters, and
report the trial information and results to the partner.
（6）Keep clear and accurate records of visits, tests not performed, and inspections not made by
the investigator, and whether or not corrections have been made for errors and omissions.
（7）Complete a written monitoring report after each visit, which should state the date and time
of the monitoring, the name of the monitor, and the findings of the monitoring.
12.3
Requirements for Investigators

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（1）The investigators participating in the clinical trial must have the professional expertise,
qualification and ability of the clinical trial, after qualification examination, and the personnel
requirements are relatively fixed;
（2）Before patient enrollment, the investigator should explain the significance of the clinical
study to the enrollee or family members, obtain their consent and sign the informed consent form;
（3）Personally execute and supervise the conduct of the clinical study;
（4）Carefully completing the case report form (eCRF) as required;
（5）Cooperate with the regular visits of the clinical supervisor appointed by the collaborator or
his/her representative;
（6）Keeping complete records of laboratory tests, clinical records, and original medical records
of patients;
（7）In the event of a serious adverse event, the investigator must determine the cause and deal
with it accordingly, and report it to the study leader;
（8）Follow-up of serious adverse events.
12.4
Audits and inspections
When the partner or a third party is commissioned to conduct an audit or inspection of the study
by the pharmacy authorities according to the needs of the trial, the original documents of the trial can
be directly accessed, and the data in the eCRF should be directly derived from the original data.
12.5
Protocol Deviation
All requirements set forth in the study protocol must be strictly enforced. Any intentional or
unintentional deviation or violation of the trial protocol and GCP principles can be categorized as
protocol deviation. The supervisor should fill in the protocol deviation record by the investigator or
the supervisor if protocol deviation is found in the course of supervision, recording in detail the time
of discovery, the time and process of the event, the reason and the corresponding treatment measures,
which should be signed by the researcher and notified to the Ethics Committee and the collaborators.
In the statistical analysis report and summary report, the impact of the occurred protocol deviations on
the final data and conclusions was analyzed and reported.
When serious protocol deviations occur, they should be evaluated. If necessary, the collaborators
may terminate the study early.
13
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Clinical Trial Protocol
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