Neoadjuvant Immunotherapy With Intratumoral Tavokinogene Telseplasmid (Tavo) Plus Electroporation in Combination With Intravenous Nivolumab in Patients With Operable Locally- Regionally Advanced Melanoma
Phase: PHASE2
Conditions: Melanoma
Sponsor: H. Lee Moffitt Cancer Center and Research Institute

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08 
 
 
 
 
CLINICAL STUDY PROTOCOL 

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Protocol Title: 
Neoadjuvant Immunotherapy with Intratumoral Tavokinogene 
Telseplasmid (Tavo) plus Electroporation in Combination with 
Intravenous Nivolumab in Patients with Operable Locally- 
Regionally Advanced Melanoma 
MCC Number: 
20313 
Compound Number: 
Tavokinogene telseplasmid (tavo) with Electroporation (EP) 
Nivolumab, an anti-programmed cell death 1 (anti-PD-1) antibody 
Study Phase: 
II 
Sponsor Name: 
Source of Funding: 
Moffitt Cancer Center 
OncoSec Medical Incorporated 

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Principal Investigator 
Sub-Investigators 
Statistician 
Ahmad Tarhini, MD, PhD 
Moffitt Cancer Center 
10920 McKinley Dr., Tampa, FL 33612 
Tel: 813-745-8581; Fax: 813-745-5725 
Email: Ahmad.Tarhini@moffitt.org 
Vernon K. Sondak, MD 
Moffitt Cancer Center 
Email: Vernon.Sondak@moffitt.org 
Jonathan S.Zager, MD 
Moffitt Cancer Center 
Email: Jonathan.Zager@moffitt.org 
Amod A. Sarnaik, MD 
Moffitt Cancer Center 
Email: Amod.Sarnaik@moffitt.org 
Nikhil I. Khushalani, MD 
Moffitt Cancer Center 
Email: Nikhil.Khushalani@moffitt.org 
Zeynep Eroglu, MD 
Moffitt Cancer Center 
Email: Zeynep.Eroglu@moffitt.org 
Joseph Markowitz, MD, PhD 
Moffitt Cancer Center 
Email: Joseph.Markowitz@moffitt.org 
Andrew Brohl, MD 
Moffitt Cancer Center 
Email: Andrew.Brohl@moffitt.org 
Ann Chen, PhD 
Moffitt Cancer Center 
Email: Ann.Chen@moffitt.org 

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Protocol Title 
Neoadjuvant Immunotherapy with Intratumoral Tavokinogene 
Telseplasmid (Tavo) plus Electroporation in Combination with 
Intravenous Nivolumab in Patients with Operable Locally-Regionally 
Advanced Melanoma 
Protocol Number 
MCC 20313 
Amendment No. (if 
applicable) 
NA 
IND Number(s): 
19502 
 
 

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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Protocol Title 
Neoadjuvant Immunotherapy with Intratumoral Tavokinogene 
Telseplasmid (Tavo) plus Electroporation in Combination with 
Intravenous Nivolumab in Patients with Operable Locally- 
Regionally Advanced Melanoma 
Protocol Number 
MCC 20313 
Version and Date 
v.26JUL2023 
Amendment No. (if 
applicable) 
NA 
Regulatory Agency 
Identifier Number(s): 
 
 
 STATEMENT OF COMPLIANCE 
 
 
 
The trial will be conducted in accordance with the ICH E6, the Code of Federal Regulations on the 
Protection of Human Subjects (45 CFR Part 46), and the Supporting Agency Terms. The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place without prior 
agreement from the sponsor and documented approval from the Institutional Review Board, except 
where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in 
the conduct of this study have completed Human Subjects Protection Training. 
 
 
I agree to ensure that all staff members involved in the conduct of this study are informed of their 
obligation to meet the above commitments. 
 
 
 
 
Principal Investigator:   Ahmad Tarhini, MD, PhD 
Print/Type Name 
 
 
Signed: 
                                                                          Date: See signature_ 

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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
PROTOCOL APPROVAL FORM ..................................................................................................1 
1.1. 
Synopsis ......................................................................................................................10 
1.2. 
Schema ........................................................................................................................13 
1.3. 
Schedule of Activities (SoA) ......................................................................................14 
2. 
INTRODUCTION ......................................................................................................20 
2.1. 
Study Rationale ...........................................................................................................20 
2.2. 
Background .................................................................................................................20 
2.3. 
Benefit/Risk Assessment ............................................................................................21 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................23 
4. 
STUDY DESIGN .......................................................................................................25 
4.1. 
Overall Design ............................................................................................................25 
4.2. 
Scientific Rationale for Study Design ........................................................................26 
4.3. 
Justification for Dose ..................................................................................................26 
4.3.1. 
Tavo Dose Selection Rationale ...................................................................................26 
4.3.2. 
Electroporation Parameters Rationale ........................................................................27 
4.3.3. 
Nivolumab Dose Selection Rationale .........................................................................28 
4.4. 
End of Study Definition ..............................................................................................28 
5. 
STUDY POPULATION .............................................................................................29 
5.1. 
Inclusion Criteria ........................................................................................................29 
5.2. 
Exclusion Criteria .......................................................................................................30 
5.3. 
Screen Failures............................................................................................................33 
5.4. 
Registration Procedures ............................................................................................. 29 
5.4.1 
Enrollment..................................................................................................................29 
6. 
STUDY INTERVENTION ........................................................................................34 
6.1. 
Study Intervention(s) Administered ...........................................................................34 
6.1.1. 
Medical Devices .........................................................................................................35 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................35 
6.3. 
Study Intervention Compliance ..................................................................................36 
6.4. 
Concomitant Therapy .................................................................................................36 
6.4.1. 
Prohibited Concomitant Medications .........................................................................37 

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6.5. 
Intervention after the End of the Study .......................................................................38 
6.6. 
Stopping Rules and Toxicity Management Guidelines ..............................................38 
6.6.1. 
Tavo ............................................................................................................................38 
6.6.2. 
Nivolumab ..................................................................................................................39 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................41 
7.1. 
Discontinuation of Study Intervention ........................................................................41 
7.1.1. 
Temporary Discontinuation ........................................................................................41 
7.2. 
Subject Discontinuation/Withdrawal from the Study .................................................41 
7.3. 
Lost to Follow up ........................................................................................................42 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................43 
8.1. 
Efficacy Assessments .................................................................................................43 
8.1.1. 
Complete Pathologic Response (pCR) .......................................................................43 
8.1.2. 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and immune 
RECIST (iRECIST) ....................................................................................................43 
8.1.3. 
Lesion Photographs and Unidimensional Clinical Measurements .............................43 
8.2. 
Safety Assessments .....................................................................................................44 
8.2.1. 
Medical History and Concomitant Medications .........................................................44 
8.2.2. 
Eastern Cooperative Oncology Group (ECOG) Performance Status .........................44 
8.2.3. 
Durable Procedural Pain Assessment .........................................................................44 
8.2.4. 
Physical Examinations ................................................................................................45 
8.2.5. 
Vital Signs ..................................................................................................................45 
8.2.6. 
Clinical Safety Laboratory Assessments ....................................................................46 
8.3. 
Adverse Events and Serious Adverse Events .............................................................46 
8.3.1. 
Time Period and Frequency for Collecting AE, SAE and ECI Information...............46 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................47 
8.3.3. 
Follow-up of AEs, ECIs and SAEs .............................................................................47 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................48 
8.3.5. 
Pregnancy ...................................................................................................................49 
8.3.6. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs ...............................................................................................................50 
8.3.7. 
Medical Device Incidents (Including Malfunctions) ..................................................51 
8.3.7.1. 
Time Period for Detecting Medical Device Incidents ................................................51 

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8.3.7.2. 
Follow-up of Medical Device Incidents .....................................................................51 
8.3.7.3. 
Prompt Reporting of Medical Device Incidents to Sponsor .......................................51 
8.3.7.4. 
Regulatory Reporting Requirements for Medical Device Incidents ...........................51 
8.4. 
Biomarkers ..................................................................................................................52 
9. 
STATISTICAL CONSIDERATIONS .......................................................................53 
9.1. 
Statistical Hypotheses .................................................................................................53 
9.2. 
Sample Size Determination ........................................................................................53 
9.3. 
Populations for Analyses ............................................................................................53 
9.4. 
Statistical Analyses .....................................................................................................53 
9.4.1. 
Subject Disposition .....................................................................................................54 
9.4.2. 
Demographic and Baseline Characteristics ................................................................54 
9.4.3. 
Efficacy Analyses .......................................................................................................54 
9.4.4. 
Safety Analyses ..........................................................................................................55 
9.4.5. 
Other Analyses ............................................................................................................55 
9.5. 
Interim Analyses .........................................................................................................55 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................56 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .....................56 
10.1.1. 
Regulatory and Ethical Considerations.......................................................................56 
10.1.2. 
Informed Consent Process ..........................................................................................56 
10.1.3. 
Data Protection ...........................................................................................................57 
10.1.4. 
Dissemination of Clinical Study Data ........................................................................57 
10.1.5. 
Data Monitoring Committee .......................................................................................57 
10.1.6. 
Data Quality Assurance ..............................................................................................57 
10.1.7. 
Source Documents ......................................................................................................58 
10.1.8. 
Study and Site Closure ................................................................................................58 
10.1.9. 
Publication Policy .......................................................................................................59 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................60 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................61 
10.3.1. 
Definition of AE .........................................................................................................61 
10.3.2. 
Definition of SAE .......................................................................................................62 
10.3.3. 
Definition of Events of Clinical Interest .....................................................................62 

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10.3.4. 
Definition of Suspected and Unsuspected Adverse Reaction .....................................63 
10.3.5. 
Recording and Follow-Up of AE and/or SAE ............................................................63 
10.3.6. 
Reporting of SAEs ......................................................................................................65 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................67 
10.5. 
Appendix 5: Collection of Human Samples for Immune Monitoring ........................69 
10.6. 
Appendix 6: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................................72 
10.7. 
Summary of Response Evaluation Criteria for Solid Tumors (RECIST) and 
Immune RECIST (iRECIST) ......................................................................................74 
10.7.1. 
RECIST v1.1 ...............................................................................................................74 
10.7.1.1. 
Evaluation of Overall Response with RECIST v1.1 ..................................................76 
10.7.2. 
Immune-Related RECIST (iRECIST) ........................................................................76 
10.7.3. 
Measurable Disease and Lesions Definitions .............................................................79 
10.7.4. 
Tools for Tumor Assessments ....................................................................................80 
10.7.4.1. 
Tumor Imaging for Evaluation of Response...............................................................80 
10.8. 
Surgical Considerations ..............................................................................................81 
10.8.1. 
Primary Excision or Primary Cutaneous Melanoma ..................................................81 
10.8.2. 
Regional Lymphadenectomy ......................................................................................82 
10.8.2.1. 
Head and Neck Lesions ..............................................................................................82 
10.8.2.2. 
Upper Extremity .........................................................................................................82 
10.8.2.3. 
Lower Extremity .........................................................................................................82 
10.8.2.4. 
Lymphadenectomy for Nodal Recurrence ..................................................................82 
10.8.3. 
Surgery for Distant Cutaneous/Subcutaneous or Nodal Metastases ...........................82 
10.9. 
Appendix 9: Abbreviations .........................................................................................83 
11. 
REFERENCES ...........................................................................................................97 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: Neoadjuvant Immunotherapy with Intratumoral Tavokinogene Telseplasmid 
(tavo) plus Electroporation in Combination with Intravenous Nivolumab in Patients with 
Operable Locally-Regionally Advanced Melanoma. 
Short Title: Neoadjuvant Immunotherapy of Tavo-EP and Nivolumab in Operable Melanoma 
Rationale: Treatment of advanced melanoma has recently been transformed by the approval of 
several novel agents (immune checkpoint inhibitors and molecular‐targeted agents) that are more 
effective than conventional chemotherapy. Despite the clinical benefit in the responding 
subgroup to anti-programmed cell death protein 1 (PD-1) agents (nivolumab, pembrolizumab), 
the numbers indicate that a significant rate of subjects still do not respond to treatment, thus new 
agents are needed to increase the tumor response in advanced melanoma to improve response 
rates. A combination therapy of an anti-PD-1 drug with an agent capable of driving an effective 
T cell response, such as interleukin‐12 (IL-12) may increase the immunogenicity and cytotoxic T 
lymphocytes (CTL) activity leading to an enhanced response. 
Intratumoral injection of tavokinogene telseplasmid (tavo; IL-12 plasmid) followed by in vivo 
electroporation (tavo-EP or GenPulse® tavo), the investigational therapy, is a gene therapy 
approach designed to produce a localized expression of the pro-inflammatory cytokine IL-12 in 
the tumor microenvironment. The current study is designed to evaluate the safety and efficacy of 
neoadjuvant immunotherapy of intratumoral tavo-EP in combination with intravenous (IV) 
nivolumab followed by surgery and adjuvant phase with nivolumab monotherapy in subjects 
with operable, locally-regionally advanced melanoma. Neoadjuvant evaluation of anti-PD-1 
agent nivolumab in combination with tavo may improve the clinical outcome in these subjects as 
it can transform poorly infiltrated/non-inflamed tumors into immunologically active lesions. 
Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary 
• To assess the complete pathologic 
response rate (pCR) of intratumoral 
tavo-EP in combination with IV 
nivolumab (collectively ‘the combined 
treatment’) in subjects with operable 
locally-regionally advanced melanoma. 
• pCR defined as proportion of subjects 
with no viable tumor on histologic 
assessment at definitive surgery 
Secondary 
• To assess 
(a) radiologic/clinical preoperative 
response rate, 
• Objective response rate (ORR) assessed 
by Investigator based on Response 
Evaluation Criteria In Solid Tumors 
(RECIST) v1.1 at 12 weeks of 

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Objectives 
Endpoints 
(b) Relapse Free Survival (RFS) and 
(c) Overall Survival (OS). 
Neoadjuvant phase (preoperative, 
unconfirmed) 
• Duration of response (DOR) 
• RFS 
• Immune best overall response rate 
(iBORR) assessed by Investigator based 
on iRECIST (optional) 
• OS 
• To assess safety and tolerability of the 
combined treatment as neoadjuvant 
therapy in subjects with operable locally- 
regionally advanced melanoma. 
• Frequency, duration and severity of 
adverse events (AEs) and serious adverse 
events (SAEs); 
• Number of subjects with events of clinical 
interest (ECIs); 
• Number of subjects who discontinued due 
to AEs 
• Incidence and shifts of clinically 
significant laboratory abnormalities; 
safety laboratory evaluations includes 
complete blood count (CBC), blood 
biochemistry and urinalysis. 
Exploratory 
• Immune monitoring 
• Characterization of the tumor 
microenvironment and assessment of the 
immune phenotype and function pre- and 
post-combination therapy 
Overall Design: 
This will be a Phase 2, Simon 2 stage minimax, open-label, single-arm study of neoadjuvant 
treatment of intratumoral tavo-EP plus nivolumab IV. Eligible subjects will be those with 
pathological diagnosis of operable locally-regionally advanced melanoma. 
The Treatment period will be comprised of 3 phases: 
Neoadjuvant Phase (Up to 3 x 4-week cycles, total 12 weeks): At each cycle, intratumoral tavo-
EP will be administered (on Days 1 and 8) concurrently with 480 mg nivolumab IV infusion on 
Day 8 of each cycle (tavo-EP will be administered prior to nivolumab infusion). NOTE: At the 
discretion of the treating physician investigator and as discussed with the patient as a means of 
maximizing local effects of tavo, an optional additional cycle of tavo-EP can be administered 
during the 3rd week (Day 15) of each of the 3 neoadjuvant cycles in the absence of limiting 
toxicities. 

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Definitive Surgery Phase: Surgery may be scheduled about 2-4 weeks after the last dose of 
nivolumab following radiologic and clinical assessment at that point. Pathologic response will be 
determined by institutional pathologist. Under certain circumstances, the definitive surgery may 
be delayed and done after completion of additional cycles of neoadjuvant therapy if decided by 
the treating physician investigators (surgeon and medical oncologist) to be in the best interest of 
the patient (or can be done earlier if study intervention(s) was discontinued due to AEs or other 
reasons). 
Adjuvant Phase: Adjuvant therapy with nivolumab monotherapy will begin approximately 2-4 
weeks following definitive surgery, but can be later as clinically indicated to allow medical 
clearance for systemic therapy; recovery from surgery is required (Day 1 of Cycle 4 will be 
determined by the treating investigator once the subject is cleared to initiate systemic therapy). 
Nivolumab (480 mg IV infusion on Day 1 of each 4-week cycle) will be administered for up to 9 
cycles during the Adjuvant phase. 
Follow up: 
• All subjects will be followed for 4 weeks after last dose of nivolumab at End of Study (EOS) 
visit. 
• In the absence of disease progression, data from standard of care imaging will be captured 
every 3 months for 2 years post-surgery and every 6 months thereafter for up to 3 years post- 
surgery. 
• Long-term survival status will be performed every 6 months (by phone) for up to 5 years 
from study registration, unless the study is terminated early. 
Protocol Monitoring Committee (PMC) review: Moffitt PMC will monitor safety and 
efficacy parameters as specified in the PMC section later in this protocol. 
Disclosure Statement: This is a single group treatment study with 1 arm that has no masking. 
Number of Subjects: Up to 33 subjects; in Simon minimax Stage 1, up to 22 subjects can be 
enrolled. If the number of pCR in Stage 1 meet the pre-specified number (N≥3 /22), enrollment 
for Stage 2 will include an additional 11 subjects (for a total of 33 subjects). 
Study Duration: For each subject, the total duration of study participation will be 1 year 
(excluding the Screening period), plus long-term follow-up of up to 5 years (until death, subject 
withdraws consent or the study was terminated): 
• Screening period: up to 4 weeks 
• Neoadjuvant phase: 12 weeks (Up to 3 x 4-week cycles) 
• Definitive surgery phase: approximately 2-4 weeks 
• Adjuvant phase: up to 36 weeks (Up to 9 4-week cycles) 
• Follow-up: up to 5 years 
Data Monitoring Committee: Yes 

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1.2.   Schema 
 
Neoadjuvant  
Phase  
(Up to 3 x4-week cycles;  
12 weeks) 
 
Definitive Surgery  
Phase  
 
 
 
Adjuvant  
Phase  
(Up to 9 x4-week cycles) 
 
 
 
 
Follow-Up  
Phase  
 
 
 
 
NOTE: At the discretion of the treating physician investigator and as discussed with the patient as a means of maximizing local effects 
of tavo, an optional additional cycle of tavo-EP can be administered during the 3rd week (Day 15) of each of the 3 neoadjuvant cycles 
in the absence of limiting toxicities. 
 
 
 
 
 
• 
Intra-tumoral TAVO-EP on Days 1, 8 and 15 (optional) of each 4-week cycle. 
• 
Nivolumab 480 mg IV infusion on Day 8 of each 4-week cycle. 
• 
On Day 8, TAVO-EP will be administered prior to nivolumab infusion. 
• 
Recovery from surgery is required (Cycle 4 Day 1 is determined by the treating 
physician investigator once the patient is cleared to initiate adjuvant systemic 
therapy; Approximately 2-4 weeks following definitive surgery but can be later 
as clinically indicated to allow medical clearance for systemic therapy).  
• 
Nivolumab 480 mg IV infusion on Day 1 of every 4-week adjuvant cycle, up to 
9 cycles.  
• 
Surgery approximately 2-4 weeks after the last dose of nivolumab. 
• 
Pathologic response will be determined by the institutional pathologist.  
• 
Surgery may be done sooner or delayed if clinically indicated based on disease 
status and recovery from adverse events as determined by the treating physician 
investigator to be in the patient’s best interest.    
• 
Subjects will follow up 4 weeks after the last dose of nivolumab (End of Study 
visit). 
• 
Long term follow-up in accordance with the standard of care. 
• 
Long term follow-up status either in clinic or via phone, but must collect 
information on disease status (relapse or not) and survival.   

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1.3. 
Schedule of Activities (SoA) 
Period/Procedure Screen
in g 
Neoadjuvant Phase 
Definitive Surgery 
Phase 
Adjuvan 
t Phase 
EOS / Early 
Discontinuatio 
n Visit [21] 
Long 
term 
follow- 
up [22] 
 
Cycl e 
1 
Cycle 
2 
Cycl e 3 
Pre
- 
Sur
ger 
y 
Surg
er y 
[18] 
Post- 
Surgery 
Recover 
y [19] 
Cycles 
4-12 [20] 
Study Day/ Day on 
cycle 
(1 cycle = 4 weeks) 
≤-
28 
1 8  
15 1 8 15 1 8 
15 
Day 1 
4 weeks after 
last dose 
~ 
every 6 
months 
Visit Window 
±2 days 
±7 days ±3 days 
±3 days 
Informed consent 
X 
Demographic and 
Medical History 
[1] 
X 
 
Inclusion/Exclusio 
n criteria review 
X 
 
Concomitant 
medications [2] 
X 
X  
 X   X  
 
X 
X 
X 
X 
ECOG 
Performance 
status 
X 
X 
X 
X 
X 
X 
Overall Survival 
status 
X 
Physical exam and 
weight 
X 
X 
X 
X
X 
X 
X 
X 
Vital signs [3] 
X 
X X X X XX X X X 
X 
X 
X 
X 
Disease staging 
[4] 
X 
Disease 
Evaluation by 
RECIST v1.1 / 
iRECIST [5] 
X 
X 
X, if disease 
progression 
Lesion 
Photographs & 
clinical 
X 
X 
X
X 
X, if disease 
progression 

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Period/Procedure Scree
ni
n 
g 
Neoadjuvant 
Phase 
Definitive Surgery 
Phase 
Adjuvan 
t Phase 
EOS / Early 
Discontinuatio 
n Visit [21] 
Long 
term 
follow- 
up [22] 
 
Cycl e 1 Cycle 
2 
Cycl e 3 
Pre
- 
Sur
ger 
y 
Surger 
y 
[18] 
Post- 
Surgery 
Recover 
y [19] 
Cycles 
4-12 [20] 
Study Day/ Day on 
cycle 
(1 cycle = 4 weeks) 
≤-
2
8 
1 8 1
5 1 8 1
5 1 8 1
5 
Day 1 
4 weeks after 
last dose 
~ 
every 6 
months 
measurements [6] 
CBC with 
Differential [7] 
X 
X 
X 
X 
X 
X 
(Cycles 
6, 9, 12) 
X 
Blood chemistry 
[8] 
X 
X 
X 
X 
X 
X 
(Cycles 
6, 9, 12) 
X 
Thyroid Function 
[9] 
X 
X 
X 
X 
X 
X 
(Cycles 
6, 9, 12) 
X 
HIV, Hepatitis B 
& C, PT, PTT [10] 
X 
Pregnancy test [11 
X 
X 
Urinalysis [12] 
X 
X 
X 
X 
X 
X 
(Cycles 
6, 9, 12) 
X 
Imaging Procedures 
Imaging [13] 
X 
X 
Per 
standard 
of care 
X, if disease 
progression & 
possible 
Per 
standar 
d of 
care 
Drug Administration 
Bi-dimensional 
tumor 
measurement for 
tavo dose 
calculation and 
tumor 
X 
X 

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Period/Procedure Screen
in g 
Neoadjuvant 
Phase 
Definitive Surgery 
Phase 
Adjuvan 
t Phase 
EOS / Early 
Discontinuatio 
n Visit [21] 
Long 
term 
follow- 
up [22] 
 
Cycl e 
1 
Cycle 
2 
Cycl e 
3 
Pre- 
Surg
er y 
Surger 
y 
[18] 
Post- 
Surgery 
Recover 
y [19] 
Cycles 
4-12 [20] 
Study Day/ Day on 
cycle 
(1 cycle = 4 weeks) 
≤-
28 
1 8 1
5 1 8 15 1 8 1
5 
Day 1 
4 weeks after 
last dose 
~ 
every 6 
months 
response[14] 
tavo-EP [25] 
X X X XX X X XX 
Pain Assessment 
[15] 
X X X XX X X XX 
Nivolumab 
X  
X  
X
X 
AE assessment 
[16] 
X 
X X X XX X X XX 
X 
X 
X 
X 
Immune 
Monitoring [17] 
Fixed tumor 
biopsy [24] 
X 
X  X
X 
 
 
X  
(if disease 
progression & 
possible) 
 
 
 
Fresh tumor 
biopsy [24] 
X 
X  X
X 
AE = adverse events; CBC = Complete Blood Count; ECOG = Eastern Cooperative Oncology Group; EOS = End of 
Study; EP = Electroporation; HIV = Human Immunodeficiency Virus; iRECIST = immune Response Evaluation 
Criteria in Solid Tumors; RECIST = Response Evaluation Criteria in Solid Tumors 
Notes to Schedule of Assessments: 
1. Medical history of the prior 3 years including any co-morbid conditions requiring active treatment as well 
as significant surgeries. Information on all interventions (systemic therapy, surgery, radiation treatment) 

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related to the subject’s melanoma cancer will also be collected. Prior immunotherapy dosing concentration 
and cycle numbers should be captured. 
2. Concomitant medication is defined as any prescription or over-the-counter preparation, including vitamins 
and supplements. All concomitant medications received within 30 days before the first dose of study 
intervention (Cycle 1, Day 1) through 30 days after the last dose of study intervention should be recorded. 
3. Vital signs to include heart rate, respiratory rate, temperature, blood pressure (systolic and diastolic). 
Height to be obtained at Screening only. 
4. Disease staging should be collected at screening for this protocol. 
5. Assessment by RECIST v1.1 will be done locally by the investigator (a) before the first dose of study 
intervention on scans performed as part of routine clinical management if they are of diagnostic quality and 
performed ≤28 days before study enrollment and (b) within 2 week prior to definitive surgery (preferred to 
be as close to surgery as possible). 
6. Photographs and unidimensional clinical measurements are required at screening and within 28 days of 
tavo dosing. All lesions will be indicated by pen and numbered before being photographed. This provides 
the baseline map of ALL accessible lesions with baseline defined as the period between signing the 
informed consent form and prior to completion of Cycle 1. Target and non-target as well as new lesion will 
be identified by a lesion number which must remain the same throughout the study. Measurable lesions that 
are target lesions must be measured by the site and data entered into electronic data capture (EDC) 
7. CBC w/differential to include: Hemoglobin, Platelets, Red Blood Cell, White Blood Cell, Basophils 
(Absolute; Abs), Eosinophils (Abs), Lymphocytes (Abs), Monocytes (Abs), Neutrophils (Abs) and 
Hematocrit. 
8. Serum Chemistry to include: sodium, potassium, CO2 or bicarbonate, chloride, albumin, alkaline 
phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase 
(LDH), total bilirubin, blood urea nitrogen (BUN), calcium, creatinine, non-fasting glucose, magnesium, 
phosphorus, and total protein, serum chemistry and hematology do not need to be repeated if the Screening 
evaluations occurred within 10 days of the C1D1, unless a clinically significant change in the interim is 
suspected. 
9. Thyroid function will include free T3, FT4 and TSH (will not need to be re-tested at C1D1 if screening 
evaluations were done within 10 days of C1D1). 
10. Virology including HIV 1/2 antibodies, HBsAg, HCV RNA (qualitative). Also, PT, PTT. These tests will be 
done only if considered clinically indicated by the treating physician. 
11. Only if considered clinically indicated by the treating physician and only for women of childbearing 
potential (i.e., postmenopausal women and women who have had a hysterectomy, oophorectomy are not of 
child- bearing potential). Local urine test must be performed within 72 hours prior to first study treatment 
and if positive, a serum test s required. An EOS urine pregnancy test will be performed and if positive, a 
serum test will be done. 
12. Urinalysis will be done only if clinically indicated. 
13. Tumor imaging will be performed in accordance with the standard of care as determined by the treating 
physician(s) and ideally should be done with the same imaging technique (computed tomography [CT ] or 
magnetic resonance imaging [MRI]; PET-CT preferred including diagnostic CT component if possible) to 
be used in a given subject throughout the study. 

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Baseline MRI brain is required to rule out metastatic disease if determined to be clinically indicated by the 
treating physician(s). CT should include the chest, abdomen and pelvis (and head and neck and all 
extremities if clinically indicated due to metastatic lesions or lymphadenopathy). All imaging will be assessed 
locally by the Investigator. 
Imaging will be performed in accordance with the standard of care as determined by the treating 
physician(s) at (a) screening imaging (can utilize scans performed 28 days prior to subject signing the 
informed consent form with a confirmatory scan within 28 days prior to Cycle 1 Day 1); (b) within a week 
prior to definite surgery. Thereafter, post-surgery, imaging will be performed per standard of care (e.g., every 3 
months for 2 years, every 6 months (± 1 week) for 3 years) and as clinically indicated up to 5 years from study 
entry. 
14. Accessible tumors for treatment will be measured in millimeter and ¼ tumor volume will be calculated in 
centimeter for each tumor selected for treatment: ¼ tumor volume = [(longest diameter in cm) 
(perpendicular diameter in cm)2]/8; a minimum of 0.1 mL per lesion for lesions <0.1 cm3 in ¼ volume will 
be administered. The maximum plasmid injection volume per subject per day will not exceed 20 mL. 
15. Intratumoral tavo-EP associated pain assessment: monitoring of pain will be performed by treating 
physician or designee (registered nurse, nurse practitioner, physician assistant) as part of the assessment on 
Days 1 and 8 of each tavo-EP treatment visit (at the start of each treatment and 5-7 minutes after EP 
procedure). Subjects will use a numeric pain rating scale to rate their pain with a start and stop time to 
capture any pain associated with EP procedure and duration. Any pain 5-7 minutes after the EP treatment 
will be evaluated on the pain scale and documented as an AE per the NCI-CTCAE v5.0 
16. AEs occurring after signing consent will be recorded 
17. Immune Monitoring details are documented in Section 10.5. Coagulation assessment (done locally) to be  
evaluated within 24 hours prior to biopsy collections if deemed clinically indicated. Coagulation 
assessment includes prothrombin time (PT), partial thromboplastin time (PTT), and international 
normalized ratio (INR). Biopsy (core or punch 3-5 mm) will be done at screening, Day 8 of cycle 1 and 
Day 1 of Cycle 2. Further, tumor will be removed at definitive surgery and some tissue will be allocated to 
immune monitoring; blood and fecal sample collection will be done at screening, Day 1 of Cycle 2, and 
then Day 1 of Cycles 6, 9 and 12 (±1 week) before treatment administration, and at disease progression (± 
2-4 weeks). Please notice that PT and PTT will be done only if considered clinically indicated by the 
treating physician. 
18. Refer to Appendix 8 (Section 10.8) for suggested guidelines on surgical management and techniques. 
These are important standard of care surgical guidelines and all investigators are strongly urged to consider 
them in the management of their patients. Under certain circumstances, the definitive surgery may be 
delayed and done after completion of additional cycles of neoadjuvant therapy if decided by the treating 
physician investigators (surgeon and medical oncologist) to be in the best interest of the patient (or earlier if 
study intervention(s) was discontinued due to AEs or other reasons). 
19. Post-surgery visit will take place approximately 2-4 weeks after surgery; subjects must be cleared by the 
treating physician investigator for  systemic standard of care adjuvant treatment with nivolumab every 4 
weeks; the Post-surgery recovery visit may serve as the start of the Adjuvant Phase, but initiation of 
systemic adjuvant therapy can be later as clinically indicated to allow medical clearance for systemic 
therapy..  
20. Adjuvant Treatment will include up to 9 cycles of nivolumab. 
21. End of Study Visit will be conducted for all enrolled subjects. EOS Visit will be conducted 4 weeks ±3 
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nivolumab or nivolumab alone). Subjects who withdraw from the study prematurely will undergo same 
assessments as EOS visit. Imaging at EOS will be in accordance with the standard of care as 
determined by the treating physician(s). 
22. Long term overall survival follow up may be via a phone call. 
23. Following enrollment/registration on the study, patients should begin protocol treatment within 7 business 
days. 
24. Research biopsy and research blood samples scheduled for Day 8 of Cycle 1 should be obtained before the 
nivolumab infusion scheduled for that day.  
25. Optional Day 15: At the discretion of the treating physician investigator and as discussed with the 
patient as a means of maximizing local effects of tavo, an optional additional cycle of tavo-EP can be 
administered during the 3rd week (Day 15) of each of the 3 neoadjuvant cycles in the absence of 
limiting toxicities. The checked procedures on the calendar would be required only if the optional Day 
15 injections were opted for. 
 
NOTE: The Investigator/Sub-Investigators are expected to make every reasonable effort to comply with the study 
calendar and schedule of activities. However, if a cycle is missed or a subject's study treatment and/or testing days 
need to be rescheduled due to the subject’s inability to comply with the study calendar (i.e., COVID-19 related 
events, hospitalizations, business and vacation travel plans, illness, transportation issues, holidays, family 
emergencies, etc.), an additional window of ± one week is available for rescheduling of study treatment and 
procedures per the discretion of the Sub- Investigator, and as needed discussed with the Investigator. 
 
NOTE: Existing FFPE tumor samples from previous and future (while on study) melanoma tumor biopsies should be 
requested if available and should be submitted for research purposes. Up to 20 unstained slides may be requested if 
available. Provision of less than 20 slides is acceptable based on availability. This applies primary melanoma tumor 
lesions and metastatic melanoma tumor lesions. These should be requested in addition to the protocol indicated research 
biopsies.   
 
NOTE: Effective July 26, 2023, blood and fecal biospecimens will no longer be collected on study.  
Rationale: (1) All patients have completed the neoadjuvant phase of the study; (2) OncoSec is no longer able to 
support this study or biospecimen collections.  
 

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2. 
INTRODUCTION 
2.1. 
Study Rationale 
The therapeutic landscape for advanced melanoma has recently been transformed by the 
approval of several novel agents (immune checkpoint inhibitors and molecular‐targeted agents) 
that are more effective than conventional chemotherapy (Michielin, 2015; Redman, 2016). 
Despite the clinical benefit in the responding subgroup to anti-PD-1 agents (nivolumab, 
pembrolizumab), the numbers indicate that significant rate of subjects still do not respond to 
treatment, thus new agents are needed to increase the tumor response in advanced melanoma to 
improve response rates. A combination therapy of an anti-PD-1 drug with an agent capable of 
driving an effective T cell response, such as IL-12 may increase the immunogenicity and CTL 
activity to enhance response. 
Intratumoral injection of tavokinogene telseplasmid (tavo; IL-12 plasmid) followed by in vivo 
electroporation (tavo-EP or ImmunoPulse® tavo), the investigational therapy, is a gene therapy 
approach designed to produce a localized expression of pro-inflammatory cytokine IL-12 in the 
tumor microenvironment. The current study is designed to evaluate the safety and efficacy of 
neoadjuvant immunotherapy with intratumoral tavo-EP in combination with IV nivolumab 
followed by surgery and adjuvant phase with nivolumab in subjects with operable locally- 
regionally advanced melanoma. Neoadjuvant evaluation of anti-PD-1 agent nivolumab in 
combination with tavo may improve the clinical outcome in these subjects as it can transform 
poorly infiltrated/non-inflamed tumors into immunologically active lesions. 
2.2. 
Background 
Human IL-12 is a 70 kilodalton protein consisting of two subunits linked by a disulfide bond 
(Kobayashi, 1989). It is a potent pleotropic cytokine, capable of driving cell-mediated immunity 
through multiple parallel mechanisms, including activation of natural killer (NK) cells and CTLs 
as well as inhibition of regulatory T cells and myeloid-derived suppressor cells (MDSCs) 
(Kobayashi, 1989; Brunda, 1993; Steding, 2011). Also, as a potent inducer of interferon-gamma 
(IFN-γ), IL-12 can drive upregulation of antigen processing and presentation machinery (APM) 
within tumors (Zika, 2005; Kerkar, 2011). 
Intratumorally injected tavo is taken up by tumor cells by electroporation (short electrical pulses 
to increase membrane permeability) using the OncoSec Medical System (OMS), a medical 
device consisting of a handle and sterile disposable electrode applicator tips containing a circular 
6 stainless steel needle array (with diameter of either 0.5 cm or 1.0 cm) (OMS Applicator) and an 
electric pulse device (OMS Generator). EP is a physical method of delivery of compounds to 
tissues in vivo and was first reported to transfect cells in vivo with plasmid DNA in 1991 when 
reporter gene expression was seen in skin cells of mice (Titomirov, 1991). EP exposes target 
tissue to a sequence of brief electrical pulses of controlled voltage and duration, leading to 
transient increased permeability of the cell membrane. This allows for enhanced movement of 
molecules, such as plasmid DNA, into the intracellular space. 
The tavo nonclinical program consists of a battery of in vivo tumor models, biodistribution 
studies and non-GLP toxicology studies. The tavo-EP clinical development program includes 9 
clinical studies in 153 subjects with different malignancies with data available for 153 subjects in 

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the clinical database, of whom 106 received tavo-EP as monotherapy and 47 received tavo-EP in 
combination with IV pembrolizumab. 
A detailed description of nonclinical and clinical studies, chemistry, pharmacology, efficacy, and 
safety is provided in the tavo Investigator’s Brochure (IB). 
Nivolumab (OPDIVO; Bristol-Myers Squibb Company) is a fully human IgG4 anti-PD-1 
blocking monoclonal antibody that has shown clinical activity in subjects with advanced 
melanoma, non-small cell lung cancer, renal cell cancer, colorectal cancer, bladder cancer, head 
and neck cancer and other advanced malignancies (Topalian, 2012). In the adjuvant setting, 
nivolumab was associated with an improved recurrence-free survival (RFS) compared with 
ipilimumab (HR 0.65; CI: 0.51-0.83; P < 0.001) in a phase 3 study (CHECKMATE-238) that 
randomized 906 subjects with resected Stage IIIB-IV melanoma to either one year of nivolumab 
(3 mg/kg every 2 weeks) or ipilimumab (10 mg/kg every 3 weeks times 4 doses followed by 
every 12 weeks). Furthermore, the rate of treatment-related Grade 3-4 toxicity was 14.4% with 
nivolumab versus 42.6% in subjects treated with ipilimumab (Weber, 2017). Nivolumab was 
recently approved in the US as an adjuvant treatment for subjects with completely resected 
melanoma with lymph node involvement or metastatic disease. For additional information refer 
to the Package Insert (OPDIVO®, 2018). 
 
2.3. 
Benefit/Risk Assessment 
As indicated above, anti-PD-1 monoclonal antibody nivolumab was recently approved by the 
FDA for the treatment of melanoma in the adjuvant setting based on improvement in RFS in a 
randomized, double-blind study CHECKMATE-238. The most common adverse reactions in the 
study (reported in at least 20% of nivolumab-treated subjects) were fatigue, diarrhea, rash, 
musculoskeletal pain, pruritus, headache, nausea, upper respiratory infection, and abdominal 
pain. The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis 
(6%), and hepatitis (3%). For information about the known and expected benefits and risks and 
reasonably expected AEs of nivolumab refer to the Package Insert (OPDIVO®, 2018). 
Anti-tumor activity of intratumoral tavo-EP demonstrated that intratumoral tavo-EP leads to 
significant increases in intratumoral IL-12 concentration without systemic IL-12 exposure, or 
systemic immune-related toxicities. Moreover, intratumoral tavo-EP in melanoma has been 
shown to not only increase intratumoral expression of IL-12 but also genes related to innate 
immunity, antigen presentation and anti-tumor adaptive immune responses. Efficacy data with 
tavo-EP in combination with anti-PD-1 monoclonal antibody pembrolizumab (OMS-I102) in 
subjects with melanoma that has low tumor infiltrating lymphocytes (TILs) showed a BORR of 
50% (11/22); a CR of 41% (9/22); a disease control rate (DCR; CR + PR + stable disease [SD]) 
of 59% (13/22); progression free survival (PFS) of 57% at 15 months; and duration of response 
(DOR) of 100% (11/11) (Algazi, 2016; Algazi, 2016 AACR; Algazi, 2017). 
The most frequently reported treatment-related adverse event (AE) is transient pain in 
association with the EP procedure. Other common treatment-related AE (incidence of ≥10% of 
subjects) treated with intratumoral tavo-EP as monotherapy were pain, injection site 
inflammation and injection site discoloration, most of which have been Grade 1 or 2 in severity. 
One tavo-EP monotherapy subject experienced a treatment-related serious adverse drug reaction 
(ADR), a Grade 3 cellulitis and 1 subject died due to tumor hemorrhage assessed by the 

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Investigator as unlikely related to study treatment. Two monotherapy subjects discontinued the 
study due to treatment related procedural pain. 
For the combination therapy study (tavo-EP with pembrolizumab; CC-15852/OMS-I102), the 
common study treatment-related TEAEs (incidence of >10%) were fatigue, dizziness, myalgia, 
injection site pain, pruritus, nausea, procedural pain, arthralgia, and diarrhea, all of which have 
been Grade 1 or 2. No deaths have been reported among subjects. One subject reported a Grade 3 
cellulitis assessed by the investigator as related to tavo-EP and unlikely related to 
pembrolizumab. Two subjects discontinued treatment due to AE; 1 subject experienced Grade 2 
diarrhea, assessed by the investigator as not related to tavo-EP and possibly related to 
pembrolizumab; 1 subject experienced 2 AEs, a Grade 2 confusional state assessed by the 
investigator as possible related to tavo-EP and pembrolizumab, and a Grade 1 paresthesia, 
assessed by the investigator as not related to tavo-EP and pembrolizumab. 
Most subjects report discomfort and/or pain associated with EP, even with administration of 
local anesthesia, oral pain killers, and anxiolytics. The BP-associated pain, described as an 
"electrical shock" or "sharp punch" is experienced only during administration of the EP pulses 
and is transient. It is recommended that the area be iced or treated with a topical numbing agent. 
Individuals should be properly informed to prepare for the EP discomfort and pain sensation 
before treatment in procedures where general anesthesia is not indicated or desired. For subjects 
with low pain thresholds or with large treatment areas requiring multiple EPs, the subject may 
receive Ativan (Iorazepam) as prophylaxis. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of intratumoral tavo-EP may be found in the IB. 

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3. 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Primary 
• To assess the complete pCR of 
intratumoral tavo-EP in combination with 
IV nivolumab (collectively ‘the combined 
treatment’) in subjects with operable 
locally-regionally advanced melanoma. 
• pCR defined as proportion of subjects 
with no viable tumor on histologic 
assessment at definitive surgery. 
Secondary 
• To assess 
(a) radiologic/clinical preoperative 
response rate, 
(b) RFS and 
(c) OS. 
• ORR assessed by Investigator based on 
RECIST v1.1 at 12 weeks during the 
Neoadjuvant phase (preoperative, 
unconfirmed). 
• Duration of response (DOR) 
• RFS 
• iBORR assessed by Investigator based on 
iRECIST (optional). 
• OS 
• To assess safety and tolerability of the 
combined treatment as neoadjuvant 
therapy in subjects with operable locally- 
regionally advanced melanoma. 
• Frequency, duration and severity of AEs 
and SAEs. 
• Number of subjects with ECIs. 
• Number of subjects who discontinued 
due to AEs. 
• Incidence and shifts of clinically 
significant laboratory abnormalities; 
safety laboratory evaluations includes 
CBC, blood biochemistry and urinalysis. 
• To assess the risk of surgical delay (either 
due to toxicity and/or tumor progression). 
• Definitive surgery will be planned at 
about 12 weeks. Patients will be 
monitored for surgical delay (either due 
to toxicity and/or tumor progression). 
Exploratory 
• Immune monitoring. 
• Characterization of the tumor 
microenvironment and assessment of 

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Objectives 
Endpoints 
immune phenotypes and function 
associated with treatment 

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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This will be a Phase 2, Simon 2 stage minimax, open-label, single-arm study of neoadjuvant 
treatment of intratumoral tavo-EP plus nivolumab IV. Eligible subjects will be those with 
pathological diagnosis of operable locally-regionally advanced melanoma. The purpose and 
procedures of the study will be fully explained to potential subjects. Those wishing to enroll in 
the study will sign a written informed consent prior to initiating any study-related evaluations or 
procedures. Screening must be completed within 28 days prior to initiation of the study treatment 
(i.e. Cycle 1 Day 1; C1D1). 
The Treatment period will be comprised of 3 phases: 
Neoadjuvant Phase (Up to 3 x 4-week cycles, total 12 weeks): At every cycle, intratumoral tavo-
EP will be administered (on Days 1 and 8) concurrently with 480 mg nivolumab IV infusion on 
Day 8 of each cycle (tavo-EP will be administered prior to nivolumab infusion). 
Definitive Surgery Phase: Surgery may be scheduled about 2-4 weeks after the last dose of 
nivolumab following radiologic and clinical assessment at that point. Pathologic response will be 
determined by institutional pathologist. Refer to Appendix 8 (Section 10.8) for suggested 
guidelines on surgical management and techniques. These are important standard of care surgical 
guidelines and all investigators are strongly urged to consider them in the management of their 
patients. Under certain circumstances, the definitive surgery may be delayed and done after 
completion of additional cycles of neoadjuvant therapy if perceived by the treating physician 
investigators (surgeon and medical oncologist) to be in the best interest of the patient (or earlier 
if study intervention(s) was discontinued due to AEs or other reasons). 
Adjuvant Phase: Adjuvant therapy with nivolumab monotherapy will begin approximately 2-4 
weeks following definitive surgery; recovery from surgery is required (Day 1 of Cycle 4 will be 
determined by the treating investigator once the subject is cleared to initiate systemic therapy). 
Nivolumab (480 mg IV infusion on Day 1 of each 4-week cycle) will be administered for up to 9 
cycles during the Adjuvant phase. 
In Simon minimax Stage 1, up to 22 subjects can be enrolled. If the number of responders in 
Stage 1 meet the pre-specified number (N≥3 //22), enrollment for Stage 2 will include an 
additional 11 subjects (for a total of 33 subjects). 
All subjects will be followed for 4 weeks after last dose of nivolumab at EOS visit; data from 
standard of care imaging will be captured (every 3 months for 2 years post-surgery and every 6 
months thereafter for up to 3 years post-surgery); long-term survival status will be determined 
every 6 month (by phone) for up to 5 years unless the study is terminated early. 
Written IND safety reports will be submitted to the FDA by the IND sponsor, for serious, unexpected 
suspected adverse reactions within 15 calendar days of learning of its occurrence. If the event is fatal or is 
deemed to be life threatening, the report will be made within 7 calendar days. The IND sponsor will also 
make an assessment of whether the event constitutes an unanticipated problem posing risks to subjects or 
others (UP). This assessment will be provided to the IRB, which, in turn will make a final determination. 
If the IRB determines an event is a UP it will notify the appropriate regulatory agencies and institutional 
officials. 

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4.2. 
Scientific Rationale for Study Design 
Pooled data from 4 ongoing neoadjuvant therapy studies at 3 large melanoma centers 
participating in the International Neoadjuvant Melanoma Consortium indicated that neoadjuvant 
targeted and immunotherapy are associated with a high pCR rate in stage III melanoma (Tetzlaff, 
2018). Preliminary data suggest pCR correlates with improved RFS, particularly in those with 
pCR with immunotherapy (Menzies, 2017). Neoadjuvant evaluation of anti-PD-1 agent 
nivolumab in combination with tavo may improve the clinical outcome in subjects with 
advanced operable melanoma as it can transform poorly infiltrated/non-inflamed tumors into 
immunologically active lesions. The response rate (both pathologic and radiologic) in this setting 
is important to define to guide the field on the best approach for managing clinically evident 
operable disease. It will also provide needed data that would guide future nivolumab-based 
active combinations that may have important applicability in this setting. 
The pCR rate (defined as no viable tumor on histologic assessment at surgery) is the most 
clinically meaningful endpoint with this immunotherapeutic agent given the implications on both 
the operability of the disease and on survival. The preoperative radiologic response rate will also 
be informative and clinically meaningful and such responses are expected to translate into 
durable survival benefits based on the current experience with nivolumab. 
4.3. 
Justification for Dose 
4.3.1. 
Tavo Dose Selection Rationale 
Dose: Phase 1 clinical study to evaluate the safety and efficacy of a single cycle of intratumoral 
tavo-EP as a monotherapy in subjects with unresectable or metastatic melanoma showed 19 of 24 
(79%) subjects enrolled on this study had additional sites of disease outside of the treated lesions 
(distant disease), and these subjects were therefore evaluated for distant response to therapy. In 
53% there was evidence of a systemic response resulting in either stable disease, or objective 
regression of untreated lesions. In addition, in 3/19 subjects (15%) all of the distant lesions 
regressed completely in either the absence of any other systemic antitumor therapy (n=2) or 
following treatment with dacarbazine (n=1). Thus, the tavo selected dose (concentration of 
0.5 mg/mL at a dose volume of approximately ¼ of the calculated lesion volume) is based on the 
dose cohort that yielded the highest proportion of responders. 
Intratumoral administration: Systemic administration of IL-12 in multiple clinical studies in 
recombinant form (Atkins, 1997; Leonard, 1997; Hurteau, 2001) or via IL-12-expressing 
adoptive cell therapies (Rosenberg, 2015; National Cancer Institute, 2017) led to widespread, 
severe immune-related toxicities and death, but little or no anti-cancer efficacy in nearly all solid 
tumor indications. 
To mitigate these toxicities, a multitude of localized delivery approaches have been explored 
(Sangro, 2004; van Herpen, 2004; Heinzerling, 2005; Mahvi, 2007; Anwer, 2010; Anwer, 2013; 
Linette, 2013; Nemunaitis, 2013; Nemunaitis, 2014; Lebel, 2015; Lebel, 2016; 2016; McArthur, 
2016). The best efficacy demonstrated to date by any of these approaches was 20-50% ORR; 
these responses were accompanied by systemic Grade 3 or higher drug-related SAEs in 16-50% 

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of subjects across all indications tested (Linette, 2013; Nemunaitis, 2013; Nemunaitis, 2014; 
Lebel, 2015; Lebel, 2016; 2016; McArthur, 2016). In all studies where significant IL-12-related 
efficacy was achieved, related toxicities led to removal of at least some subjects from therapy or, 
in several cases, halt of the studies (Atkins, 1997; Leonard, 1997; Hurteau, 2001; Heinzerling, 
2005; Mahvi, 2007; Anwer, 2010; Rudman, 2011; Anwer, 2013; Linette, 2013; Nemunaitis, 
2013; Nemunaitis, 2014; Lebel, 2015; Rosenberg, 2015; Lebel, 2016; 2016; McArthur, 2016; 
National Cancer Institute, 2017). 
As a monotherapy in advanced melanoma, ImmunoPulse® tavo yielded 33% best ORR, with 
62% of subjects showing regression of untreated lesions (Daud, 2014; Daud, 2014). Yet, in 
contrast to other monotherapies yielding comparable objective responses (Nemunaitis, 2013; 
Nemunaitis, 2014; KEYTRUDA®, 2015; Lebel, 2015; Lebel, 2016; 2016; McArthur, 2016; 
OPDIVO®, 2018), ImmunoPulse® tavo treatment has not resulted in any systemic drug-related 
SAEs (Daud, 2008; Daud, 2014; Daud, 2014; Pierce, 2014; Bhatia, 2015; Pierce, 2015). 
Regimen: Assessment of treatment on Days 1 and 8 at 4-week intervals will be evaluated in this 
study in neoadjuvant settings. Since IL-12 has an estimated half-life of 2-12 hours (Atkins, 1997; 
Portielje, 2005; Arkenau, 2011; Bhatia, 2015), any IL-12 that may enter the systemic circulation 
would be cleared within the 4-week cycle duration, and thus, cumulative increases in IL-12 
should not be of concern when applying a 4-week cycle frequency with tavo and EP for 
co-localization of placement. 
 
4.3.2. 
Electroporation Parameters Rationale 
Of the methods available for in vivo gene delivery, EP is associated with high transfection 
efficiency and is a clinically developed platform (Potter, 2003). 
Exposure of cells or tissue to brief, controlled electrical pulses at a specified electrical voltage 
causes a transient increase in cell membrane permeability, allowing macromolecules such as 
DNA to enter the cell and be expressed (i.e., transfection) (Gehl, 2003). EP-mediated 
transfection with plasmid DNA (pDNA) represents a non-viral gene therapy. EP has been used 
extensively to deliver pDNA to cartilage, blood, muscle, epithelial and loose connective tissue 
(Grossin, 2003; Weissinger, 2003; Kunieda, 2004; Hirao, 2008; Yuan, 2008). EP has also been 
applied to tumors to enhance the uptake of immunomodulatory genes (Lohr, 2001; Yamashita, 
2001; Li, 2002; Lucas, 2002). 
Electrical conditions utilized for electrochemotherapy have historically been used to deliver 
immunomodulatory genes to tumor tissues (Lucas, 2002). The reasoning behind this is the 
short-duration high-intensity pulses result in less tissue damage and fewer muscle contractions 
than traditional long-duration lower-intensity gene therapy conditions (Arena, 2012). Ultimately, 
using these pulses results in a shorter duration of expression, which is inconsequential as 
activation of the immune system results in the eventual destruction of transfected tumor cells. 
Commonly, this has resulted in the use of 6 pulses at a field strength (E+) of 1500 volt/cm and 
pulse width of 100 μs at 300 msec intervals, which are the parameters used by the OMS system. 

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4.3.3. 
Nivolumab Dose Selection Rationale 
Nivolumab will be administered according to the approved label. The recommended dose of 
nivolumab is 480 mg every 4 weeks (Q4W) over 30 minutes infusion. This dose was recently 
approved in the United States for the adjuvant treatment of high-risk melanoma patients. 
4.4. 
End of Study Definition 
A subject is considered to have completed the study if he/she has completed all phases of the 
study including the end of study (EOS) visit. 
The end of the study is defined as the date of the last survival contact of the last subject in the 
study. 

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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
 
5.1. 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Subject must be ≥ 18 years of age inclusive, at the time of signing the informed consent. 
Type of Subject and Disease Characteristics 
2. Histologic diagnosis of melanoma belonging to the following American Joint Committee 
on Cancer (AJCC) 8th edition TNM stages (Tx or T1-4) and (N1b, N1c, N2b, N2c, N3b 
or N3c) and/or (M1a) 
3. Must be considered surgically operable and may present as any of the following groups: 
a. Primary melanoma with clinically apparent regional lymph node metastases, confirmed by 
pathological diagnosis. 
b. Clinically detected recurrence of melanoma at regional lymph node basin(s), confirmed by 
pathological diagnosis. 
c. Clinically or histologically detected primary melanoma involving multiple regional nodal 
groups, confirmed by pathological diagnosis. 
d. Clinically detected single site of nodal metastatic melanoma arising from an unknown 
primary, confirmed by pathological diagnosis. 
e. Subjects with in transit or satellite metastases with or without lymph node involvement are 
allowed if they are considered surgically resectable at Screening by the treating surgical 
oncologist. 
f. Subjects with distant cutaneous/subcutaneous, soft tissue or nodal metastases with or without 
regional lymph node involvement are allowed if they are considered potentially surgically 
resectable and can be biopsied at Screening by the treating surgical oncologist. Elevated LDH 
is not an exclusion. 
4. Subjects are eligible for this study either at presentation for primary melanoma with 
concurrent regional nodal and/or in-transit or distant metastasis, or at the time of 
clinically detected nodal, in transit, or distant recurrence. 
5. Subjects must be evaluated by standard-of-care full body imaging studies including 
positron emission tomography – computed tomography (PET-CT ;preferred; including 
diagnostic CT component if possible) or CT (if PET-CT cannot be done) as well as 
magnetic resonance imaging (MRI) of the brain (or CT if MRI cannot be done) as part of 
the initial clinical work-up at Screening (no more than 4 weeks prior to Cycle 1, Day 1). 
6. Have measurable disease based on RECIST v1.1, with at least one anatomically distinct 
lesion. Lesion or lesions must meet all the following baseline criteria: 
a. Accessible for electroporation 

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Sex 
b. Must be measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) 
c. Greater than 3 mm 
 
7. Male and Female 
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
a. Male subjects: 
Male subjects of childbearing potential must be surgically sterile, or must agree to use 
adequate method of contraception during the study and at least 5 months following the 
last day of study drug administration. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject 
b. Female subjects: 
Women of childbearing potential must have negative serum or urine pregnancy test 
within 72 hours prior to receiving the first study drug administration. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
For women of childbearing potential, must be willing to use an adequate method of 
contraception from 30 days prior to the first study drug administration and 5 months 
following last day study drug administration (either tavo or nivolumab); acceptable 
methods include hormonal contraception (oral contraceptives – as long as on stable dose, 
patch, implant, and injection), intrauterine devices, or double barrier methods (e.g. 
vaginal diaphragm/vaginal sponge plus condom, or condom plus spermicidal jelly), 
sexual abstinence or a vasectomized partner. Women may be surgically sterile or at least 
1-year post-last menstrual period. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the 
subject. 
Informed Consent 
8. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol 
 
5.2. 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Subject has a known additional malignancy that is progressing or requires active 
treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma 
of the skin that has undergone potentially curative therapy or in situ cervical cancer. Also, 

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includes patients who are considered disease-free for at least 3 years from the last 
definitive treatment for a second malignancy. 
2. Subjects who have Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies at 
Screening). HIV testing at screening is not required unless considered clinically 
indicated by the treating physician. 
3. Subjects who have active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., 
HCV RNA [qualitative] is detected at Screening); Note: Subjects who have been 
vaccinated against Hepatitis B and who are positive only for the Hepatitis B surface 
antibody are permitted to participate in the study. Hepatitis B and C testing at 
screening is not required unless considered clinically indicated by the treating 
physician. 
4. Subject has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to the first dose of 
study drug. The use of physiologic doses of corticosteroids may be approved after 
consultation with the Principal Investigator. 
5. Subject has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
6. Subject has a history of interstitial lung disease. 
7. Subject has an active infection requiring systemic therapy. 
8. Subject has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the subject’s 
participation for the full duration of the trial, or is not in the best interest of the 
subject to participate, in the opinion of the treating investigator. 
9. Subject has not recovered (i.e., > Grade 1 at Cycle 1, Day 1) from AEs due to a 
previously administered agent. 
Note: Subjects with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are an exception to this 
criterion and may qualify for the study. 
Note: If subject underwent major surgery or radiation therapy of >30 Gy, they must have 
recovered adequately from the toxicity and/or complications from the intervention prior 
to starting study combination therapy. 
10. Subject has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the study. 
11. Subjects who are pregnant or breast feeding or expecting to conceive or father children 
within the projected duration of the trial, starting with the screening visit through 5 
months after the last dose of trial treatment. 
Prior/Concomitant Therapy 
12. Subjects with electronic pacemakers or defibrillators 

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13. Subjects who have received a live-virus vaccination within 30 days of the first dose of 
treatment. Seasonal flu vaccines that do not contain live virus are permitted 
14. Subjects who have received transfusion of blood products (including platelets or red 
blood cells) or administration of colony stimulating factors (including G-CSF, GM-CSF 
or recombinant erythropoietin) within 4 weeks prior to study Cycle 1, Day 1. 
15. Previous treatment with anti-PD1 or anti-PDL1 immunotherapy. 
Prior/Concurrent Clinical Study Experience 
16. Participation in another clinical study and systemic therapy within 30 days of Cycle 1, 
Day 1. 
Note: Subjects participating in an observational study are an exception to this criterion and may 
qualify for the study with Principal Investigator approval. 
Organ Function Assessments 
17. ECOG Performance Status: >1 
18. Inadequate organ function as defined below. All screening laboratories should be 
performed within 10 days of treatment initiation. 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
<1.5 × 109/L 
Platelets 
<100 × 109/L 
Hemoglobin 
<9 g/dL or <5.6 mmol/L 
Renal 
Creatinine* OR 
>1.5 × the upper limit of normal (ULN) OR 
Measured or calculated creatinine 
clearance (CrCl) 
Glomerular filtration rate (GFR) can also 
be used instead of creatinine or CrCl 
≥60 mL/min for subject with creatinine levels 
≤1.5 × institutional ULN 
Hepatic 
Total bilirubin 
>1.5 × ULN OR direct bilirubin >ULN for 
subjects with total bilirubin levels ≤ 1.5× ULN 
Aspartate aminotransferase (AST) and 
alanine aminotransferase (ALT) 
>2.5 × ULN OR >5 × ULN for subjects with 
liver metastases 
Coagulation¥ 

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International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
>1.5 × ULN unless subject is receiving 
anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of 
anticoagulants 
Activated Partial Thromboplastin Time 
(aPTT) 
* Creatinine clearance should be calculated per institutional standard. 
¥PT, INR and PTT will be done only if considered clinically indicated by the treating 
physician. 
Other Exclusions 
19. Subject has severe hypersensitivity (≥Grade 3) to nivolumab and/or any of its excipients 
 
5.3. 
Screen Failures 
Subjects who fail to meet the entrance criteria at any time during the screening period are defined 
as screen failures. All screen failures will be recorded on the screening failure log, which 
documents the site number and screening number and reason(s) for screen failure. The screening 
failure log will be kept in the Investigator’s Site File. 
Re-screening/re-assessment outside the Screening period will be possible on a case-by-case basis 
following approval by the principal investigator. Subjects allowed to be re-screened, will be 
determined a screen failure after the second screening confirmed the subject is ineligible. 
 
 
5.4 
Registration Procedures 
Patients will be registered after meeting all entry requirements and providing a signed informed 
consent document. The date of the PI/treating physician signature on the eligibility checklist 
confirming that the patient meets the eligibility criteria is the registration date. 
5.4.1 Enrollment 
Eligible patients will be enrolled on study centrally at Moffitt Cancer Center by the Study 
Coordinator. 
When all required test results are available, complete the eligibility checklist and provide the 
checklist and the supporting documentation to the IRB approved investigator for review and 
sign-off. Once the investigator (or Sub-Investigator) has signed the eligibility checklist, 
enrollment may proceed. 
Following enrollment, patients should begin protocol treatment within 7 business days. Issues 
that would cause treatment delays should be discussed with the Principal Investigator. 

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6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study subject according to the 
study protocol. 
 
6.1. 
Study Intervention(s) Administered 
On days when both intratumoral tavo and IV nivolumab are administered, every effort will be 
made not to administer the treatments to the same arm or location. It is recommended that tavo 
will be administered first. 
 
tavo-EP 
Nivolumab 
Intervention 
Name 
Tavokinogene telseplasmid 
Electroporation 
Nivolumab 
Type 
Biologic 
Device 
Biologic 
Dose 
Formulation 
1.5 mL vials at a concentration 
of 0.5 mg/mL 
4 mL and 10 ml vials at a 
concentration of 10 mg/mL 
solution for IV infusion 
Unit Dose 
Strength(s) 
mg 
mg 
Dosage Level(s) 
Tavo will be injected on Days 
1 and 8 every 4 weeks at a dose 
volume of ¼ of the calculated 
lesion volume with a minimum 
dose volume per lesion of 0.1 
mL for lesions of volume <0.4 
cm3 
NOTE: At the discretion of the 
treating physician investigator 
and as discussed with the 
patient as a means of 
maximizing local effects of 
Tavo, an optional additional 
cycle of Tavo can be 
administered during the 3rd 
week (Day 15) of each of the 3 
neoadjuvant cycles in the 
absence of limiting toxicities. 
See Section 6.1.1. 
480 mg Q4W over 30 
minutes 
NOTE: Every effort will 
be taken to ensure that the 
infusion duration be as 
close to 30 minutes as 
possible. However, given 
the variability of infusion 
pumps from site to site, a 
window between -5 
minutes and +10 minutes is 
permitted (i.e., infusion 
time of 25 to 40 minutes). 
In patients who poorly 
tolerate the planned 
infusion time, the infusion 
time may be extended as 
clinically indicated by the 
treating team. Future 
infusion times may also be 
extended as determined to 
be clinically indicated by 
the treating physician. 
Route of 
Administration 
Intratumoral injection 
Electroporation 
IV infusion 

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tavo-EP 
Nivolumab 
IMP and NIMP 
Approved 
Sourcing 
GMP-grade tavo is 
manufactured, packaged and 
provided centrally on behalf of 
the study supporter. 
Provided centrally 
by the study 
supporter. 
Provided locally by the 
study site. 
Packaging and 
Labeling 
Study Intervention will be 
provided in vials. Each vial 
will be labeled as required per 
country requirement. 
See Section 6.1.1. 
Study Intervention will be 
provided in vials. Each vial 
will be labeled as required 
per country requirement. 
Current/Former 
Name(s) or 
Alias(es) 
ImmunoPulse tavo 
Tavokinogene telseplasmid 
OPDIVO 
 
6.1.1. 
Medical Devices 
The OMS, a medical EP device system, consists of 3 main components: (1) an Electroporation 
Generator that generates electric pulses, (2) a sterile Applicator Tip containing needle array, and 
(3) an Applicator Handle that connects to the Electroporation Generator at the proximal end and 
connects to the Applicator Tip at the distal end. The Applicator Tip contains a circular 6 needle 
array and comes in two models characterized by the needle array diameter: 0.5 cm and 1.0 cm. 
The needle length is 1.5 cm for both models and the needle insertion depth is adjustable by the 
user between 0 and 1.5 cm. An OncoSec Printer may be optionally used to generate a real-time 
event log of the electroporation treatment information used during the treatment. 
Upon user activation of the attached Foot Switch, the OMS Electroporation Generator delivers 
controlled electrical pulses in a square wave pulse pattern yielding optimal transmembrane 
potential for electroporation to occur. EP pulses occur between 6 hexagonal opposing needle 
electrodes. After the first pulse, the polarity between the opposing needle electrode pairs is 
reversed and the needle pair is pulsed again. After the initial paired pulse, the pulse delivery is 
rotated clockwise to the next opposing needle pairs until a total of 6 pulses are delivered to 
complete the EP sequence. 
OncoSec filed a Device Master File (MAF) with the Food and Drug Administration (FDA) with 
information on the electrical safety and electromagnetic compatibility, biocompatibility, sterility, 
software, packaging, etc. 
Additional details regarding handling of the device are provided in the OncoSec Medical System 
Operator’s Manual. 
6.2. 
Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Unopened drug product (tavo) sterile vials should be stored in the packaging received 
from OncoSec in a secure, continuously temperature monitored and alarmed freezer in 

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the pharmacy or other appropriate secure location at a nominal temperature of -20ºC. 
Temperature variation is allowed to a maximum temperature of -10°C. Any temperature 
excursions greater (warmer) than -10°C must be reported to the principal investigator and 
later to OncoSec. Refer to the Pharmacy Manual. 
3. The OMS Applicator and Tips will be supplied by OncoSec and should be stored in 
ambient conditions in a restricted area with limited access and may only be used on 
subjects who have been properly consented and enrolled into the investigational studies. 
Refer to the Operators Manual. 
4. Only subjects enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labeled storage conditions with access limited to the investigator 
and authorized site staff. 
5. Please refer to the Study Pharmacy Manual for tavo plasmid preparation and storage 
instructions. Briefly, Tumor size will be used to calculate the total dose per lesion and per 
subject. The number of vials needed for each intratumoral injection must be thawed at 
room temperature for approximately 5-10 minutes and mixed vigorously prior to drawing 
the solution using a sterile tuberculin syringe of appropriate size (0.3 mL to 10 mL), with 
a 25-gauge to 30-gauge 5/8-inch needle and needle cap. Additional plasmid solution can 
be withdrawn as needed to prime the syringe and deliver accurate dose(s) to the subject. 
Each treatment syringe should be visually inspected prior to injection, checking that the 
suspension is homogeneous. If the suspension does not appear homogeneous, the syringe 
should be discarded and new plasmid for treatment prepared. Unused portions of each 
vial will be discarded into approved biohazard containers and disposed of as per 
institutional requirements. The prepared formulation must be administered within 8 hours 
after thawing at room temperature. 
6. Nivolumab will be prepared per manufacturer’s instructions and should be stored as per 
the product’s package insert. 
7. The investigator is responsible for study intervention accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). 
6.3. 
Study Intervention Compliance 
Subject compliance with study intervention will be assessed at each visit. Compliance will be 
based on accountability records and an inventory of used/unused supplies. Deviation(s) from the 
prescribed dosage regimen should be recorded in the eCRF. 
 
6.4. 
Concomitant Therapy 
All treatments that the Investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care. 

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Any medications that belong to corticosteroids, immunosuppressant and/or hormonal 
replacement therapies that the subject is receiving at the time of enrollment or receives during 
the study  must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
•  
Both local and systemic analgesics and anxiolytics, as well as topical and/or injected anesthetics 
are recommended prior to the intratumoral tavo-EP procedure. Other methods, including 
conscious sedation, are also permitted and will be employed per Investigator discretion and 
standard institutional practices. Other concomitant medication may be considered on a case-by- 
case basis by the Investigator in consultation with the Principal Investigator. 
The Principal Investigator should be contacted if there are any questions regarding concomitant 
or prior therapy. 
6.4.1. 
Prohibited Concomitant Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination may 
be required. The Investigator should discuss any questions regarding this with the Principal 
Investigator. The final decision on any supportive therapy or vaccination rests with the 
Investigator and/or the subject’s primary physician. However, the decision to continue the 
subject on study therapy or vaccination schedule requires the mutual agreement of the 
Investigator, the Principal Investigator and the subject. 
Listed below are specific restrictions for concomitant therapy or vaccination during the course of 
the study: 
• 
Antineoplastic -systemic chemotherapy or biological therapy 
• 
Immunotherapy not specified in this protocol 
• 
Investigational agents other than nivolumab and tavo-EP 
• 
Radiation therapy (Note: Radiation therapy to a symptomatic solitary lesion or to the brain 
may be allowed at the Investigator’s discretion) 
• 
Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid 
(oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 

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• 
Systemic glucocorticoids (in dosing exceeding 10 mg daily of prednisone equivalent) for 
any purpose other than to modulate symptoms from an AE that is suspected to have an 
immunologic etiology. The use of physiologic doses of corticosteroids may be approved 
after consultation with the principal investigator. Note: Topical steroids are permitted. 
Inhaled steroids are allowed for management of asthma. 
Subjects who, in the assessment by the Investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study. 
All treatments that the Investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care. 
The Exclusion Criteria describes other medications that are prohibited in this study. 
There are no prohibited therapies during the post-treatment follow-up period. 
6.5. 
Intervention after the End of the Study 
No study extension is planned. 
 
6.6. 
Stopping Rules and Toxicity Management Guidelines 
6.6.1. 
Tavo 
The concentration of tavo is 0.5 mg/mL. Decision in the total number of injected lesions will be 
made at the discretion of the Principal Investigator and/or treating physician. Considerations will 
include the number of tumor lesions accessible for injection and electroporation and each 
subject’s ability to tolerate the procedure. 
Death(s) within 30 days of last dose of combination treatment on study, that are considered at 
least possibly related to study treatment, will result in temporary suspension of enrollment and 
dosing until assessed by PMC. 
If a subject experiences a Grade 4 hematological or non-hematological AE, combination 
treatment of tavo-EP and nivolumab will be discontinued until toxicity resolves to Grade ≤1 or 
baseline levels. Consult the principal investigator if a subject experiences a Grade 3 
hematological or non-hematological AE that is not resolved within 1 treatment cycle. If the AE 
resolves during the cycle such that Days 1 and 8 may take place within the allowed ±2-day 
window, then continuation of treatment may take place. Alternatively, combined treatment will 
be restarted on Day 1 of the next scheduled treatment cycle. The next treatment cycle may begin 
sooner than scheduled per Investigator’s discretion following discussion with the principal 
investigator. If the hematological toxicity does not resolve within 12 weeks of last treatment, 
permanent discontinuation should be considered for any severe or life-threatening event. Subject 
missing 2 intratumoral tavo-EP treatments in the neoadjuvant phase will be allowed to continue 
nivolumab (as monotherapy) treatment up to a total of 12 cycles (3 combination cycles and 9 
monotherapy cycles). Missed doses are permitted for inclement weather/acts of nature. 

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Please notice that tissue ulceration or cellulitis infections related to Tavo injection and/or EP are 
included under Events of Clinical Interest. Further, the occurrence of any > grade 2 skin 
ulcerations must lead to the discontinuation of injection and EP at that site. 
6.6.2. 
Nivolumab 
It is recommended to continue treatment with nivolumab for clinically stable subjects with initial 
evidence of disease progression until disease progression is confirmed. 
Dose escalation or reduction is not recommended. Dosing delay or discontinuation may be 
required based on individual safety and tolerability. Guidelines for permanent discontinuation or 
withholding of doses are described in Table 1. Detailed guidelines for the management of 
immune-related adverse reactions are described in Nivolumab package insert. 
If during the neoadjuvant phase, nivolumab is withheld or discontinued, tavo-EP can be 
administered as monotherapy (up to 3 4-week cycles) after discussion with principal investigator. 
Table 1 
Recommended treatment modifications for nivolumab 
 
Immune-related 
adverse reaction 
Severity 
Treatment modification 
Immune-related 
pneumonitis 
Grade 2 pneumonitis 
Withhold dose(s) until symptoms 
resolve, radiographic abnormalities 
improve, and management with 
corticosteroids is complete 
Grade 3 or 4 pneumonitis 
Permanently discontinue treatment 
Immune-related 
colitis 
Grade 2 diarrhea or colitis 
Withhold dose(s) until symptoms 
resolve and management with 
corticosteroids, if needed, is complete 
Grade 3 diarrhea or colitis 
Withhold dose(s) until symptoms 
resolve and management with 
corticosteroids is complete 
Grade 4 diarrhea or colitis 
Permanently discontinue treatment 
Immune-related 
hepatitis 
Grade 2 elevation in 
aspartate aminotransferase 
(AST), alanine 
aminotransferase (ALT), or 
total bilirubin 
Withhold dose(s) until laboratory 
values return to baseline and 
management with corticosteroids, if 
needed, is complete 
Grade 3 or 4 elevation in 
AST, ALT, or total 
bilirubin 
Permanently discontinue treatment 
Immune-related 
nephritis and renal 
dysfunction 
Grade 2 or 3 creatinine 
elevation 
Withhold dose(s) until creatinine 
returns to baseline and management 
with corticosteroids is complete 
Grade 4 creatinine 
elevation 
Permanently discontinue treatment 

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Immune-related 
adverse reaction 
Severity 
Treatment modification 
Immune-related 
endocrinopathies 
Symptomatic Grade 2 or 3 
hypothyroidism, 
hyperthyroidism, 
hypophysitis, 
Grade 2 adrenal 
insufficiency 
Grade 3 diabetes 
Withhold dose(s) until symptoms 
resolve and management with 
corticosteroids (if needed for symptoms 
of acute inflammation) is complete. 
Treatment should be continued in the 
presence of hormone replacement 
therapya as long as no symptoms are 
present 
Grade 4 hypothyroidism 
Grade 4 hyperthyroidism 
Grade 4 hypophysitis 
Grade 3 or 4 adrenal 
insufficiency 
Grade 4 diabetes 
Permanently discontinue treatment 
Immune-related skin 
adverse reactions 
Grade 3 rash 
Withhold dose(s) until symptoms 
resolve and management with 
corticosteroids is complete 
Grade 4 rash 
Permanently discontinue treatment 
Stevens-Johnson syndrome 
(SJS) or toxic epidermal 
necrolysis (TEN) 
Permanently discontinue treatment (see 
section 4.4) 
Other immune- 
related adverse 
reactions 
Grade 3 (first occurrence) 
Withhold dose(s) 
Grade 3 myocarditis 
Permanently discontinue treatment 
Grade 4 or recurrent Grade 
3; persistent Grade 2 or 3 
despite treatment 
modification; inability to 
reduce corticosteroid dose 
to 10 mg prednisone or 
equivalent per day 
Permanently discontinue treatment 
Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse 
Events Version 5.0 (NCI-CTCAE v5.0). 
Source: Nivolumab package insert 2018 

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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
It may be necessary for a subject to permanently discontinue study intervention prior to planned 
completion of treatment regimen (see Section 6.6 for stopping rules and toxicity management). If 
study intervention is permanently discontinued, the subject will remain in the study to be 
evaluated for up to 30 days post last dose of study intervention. See the SoA (Section 1.3 ) for 
data to be collected at the time of discontinuation of study intervention (30 days post last dose of 
study intervention). 
7.1.1. 
Temporary Discontinuation 
See Section 6.6 for stopping rules and toxicity management. 
 
7.2. 
Subject Discontinuation/Withdrawal from the Study 
Subjects are free to discontinue their participation in the study at any time and without prejudice 
to further treatment. The Investigator must withdraw any subject from the study if that subject 
requests to be withdrawn, or if it is determined that continuing in the study would result in a 
significant safety risk to the subject. 
Subjects who discontinue study drug or are withdrawn from the study prior to the first efficacy endpoint 
will not be replaced. 
The subject’s participation in the study may be discontinued due to the following reasons: 
• 
Request of Investigator 
• 
Life-threatening event or death 
• 
Subject withdrew consent 
• 
Subject is lost-to-follow-up 
The subject may discontinue study medication due to the following reasons: 
• 
Request of Investigator 
• 
AE 
• 
Treatment failure 
• 
Subject is non-compliant with study procedures or study protocol 
• 
Request of regulatory authority 
• 
Pregnancy 
• 
Other (to be specified in the electronic case report form; eCRF) 

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7.3. 
Lost to Follow up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 
• Before a subject is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 in 
Section 10.1.8. 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Immediate safety concerns should be discussed with the investigator immediately 
upon occurrence or awareness to determine if the subject should continue or 
discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the subject’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the SoA. 
 
8.1. 
Efficacy Assessments 
Planned time points for efficacy assessments are provided in the SoA. 
 
8.1.1. 
Complete Pathologic Response (pCR) 
The primary endpoint of this study is pCR, defined as no viable tumor on histologic assessment 
at definitive surgery (Tetzlaff, 2018). pCR will be evaluated locally by a certified surgical 
pathologist. 
 
8.1.2. 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and immune 
RECIST (iRECIST) 
Secondary efficacy endpoints will be evaluated using RECIST v1.1 (Eisenhauer, 2009) as 
described in Section 10.7.1 (required) and iRECIST (optional), as described in Section 10.7.2. 
Radiographic imaging will be assessed locally by the Investigator during the neoadjuvant phase 
(preoperative, unconfirmed); during the adjuvant phase, radiographic imaging and local 
assessments will be done only if feasible (as tumor is resected during surgery). 
Disease staging will be collected at original diagnosis and at screening for this protocol, prior to 
any treatment initiation. 
8.1.3. 
Lesion Photographs and Unidimensional Clinical Measurements 
Lesions photographs and unidimensional clinical measurements will be done as specified in 
SoA. Lesions will be numbered identically for each visit, each lesion will also be labelled as 
target, non-target, or new lesions (Table 8). At all study visits, lesion photography will always be 
done with a caliper/ruler and lesion identification on all accessible clinically measure lesions. 

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8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
 
8.2.1. 
Medical History and Concomitant Medications 
Any diseases in the prior three years including any co-morbid conditions requiring active 
treatment as well as significant surgeries will be documented in the medical history of the eCRF. 
Abnormal physical examination finding and/or the diagnosis of concomitant disease resulting 
from assessment at screening must be also documented in the medical history section. 
Information on all interventions (systemic therapy, surgery, radiation treatment) related to the 
subject’s melanoma cancer will also be collected.  
Concomitant medication is defined as any prescription or over-the-counter preparation, including 
vitamins and supplements. Corticosteroids, immunosuppressant and/or hormonal replacement 
therapies that the subject is receiving at the time of enrollment or receives during the study  must 
be recorded along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
8.2.2. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
The ECOG Performance Status will be used to assess subjects’ performance status by the same 
study staff (Table 2 ). The performance status will be assessed as specified in the SoA 
(Section 1.3). 
Table 2 
ECOG Performance Status 
 
ECOG PERFORMANCE STATUS 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 
8.2.3. 
Durable Procedural Pain Assessment 
Based on clinical data, it is expected that subjects will experience a transient pain associated with 
the procedure of EP that dissipates shortly thereafter. EP-associated pain assessment monitoring 

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will be performed by the treating physician or designee (registered nurse, nurse practitioner, 
physician assistant) on Days 1 and 8 of each tavo-EP treatment visit before the EP procedure and 
5 minutes after EP procedure. Only pain that persists five minutes after the end of EP procedure 
will be evaluated on numeric pain rating scale Figure 1 and documented as an AE per the 
CTCAE v5.0. 
Numeric pain rating scale measures the intensity or magnitude of sensations and subjective 
feelings and the relative strength of attitudes and opinions about specific stimuli, on a scale of 0 
to 10 with a score of zero denoting "no pain at all" and a score of 10 denoting "worst possible 
pain" (Duncan, 1989; Holdgate, 2003; Johnson, 2005; Krebs, 2007). 
Figure 1 
Numeric Pain Rating Scale 
 
 
 
 
8.2.4. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height and 
weight will also be measured and recorded. 
• A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
 
8.2.5. 
Vital Signs 
• Vital signs will be measured will include heart rate, respiratory rate, temperature, and 
blood pressure (systolic and diastolic). 
• Blood pressure and heart rate will be done at rest as per standard practice at the 
investigational site. 
• Significant findings noticed after the start of study medication and findings that 
worsen significantly, which meet the definition of an AE must be recorded on the AE 
eCRF. 
• Height to be obtained at Screening only. 

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8.2.6. 
Clinical Safety Laboratory Assessments 
• See Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA 
(Section 1.3) for the timing and frequency. 
• The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
case report form (CRF). The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which are 
not associated with the underlying disease, unless judged by the investigator to be 
more severe than expected for the subject's condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or principal investigator. 
− If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the 
investigator notified. 
− All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the protocol and the SoA. 
− If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in subject 
management or are considered clinically significant by the investigator (eg, SAE 
or AE or dose modification), then the results must be recorded in the CRF. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
AE will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the subject to discontinue the study intervention (see Section 6.6). 
8.3.1. 
Time Period and Frequency for Collecting AE, SAE and ECI Information 
All SAEs will be collected from the signing of the ICF until the follow-up visit at the time points 
specified in the SoA (Section 1.3). 
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Table 3: 
Adverse Event Observation Periods 
 
Type of 
Event 
Adverse Event 
Serious Adverse Event 
ECI with study intervention 
Reporting 
period 
From consent 
until 30 days 
after the end of 
treatment 
From consent until 30 days after 
the last dose of study treatment 
for all SAEs, and any time after 
the end of study for SAEs 
believed to be related to study 
intervention 
From consent until 30 days after 
the last dose of study treatment, 
or 30 days after the initiation of a 
new anti-cancer therapy, 
whichever is earlier 
Reporting 
Timelines to 
the Study 
supporter 
Entered into the 
clinical 
database on an 
ongoing basis 
Within 24 hours 
Within 24 hours 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF not the AE section. 
The Investigator is responsible for ensuring that all AEs observed by the Investigator or reported 
by subjects are properly captured in the subject’s medical records and reported in the eCRF. 
Investigators are not obligated to actively seek AE, ECI or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a subject has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Study supporter. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
During the study, subjects should be assessed for possible ECIs prior to each dose. Laboratory 
results should be evaluated and subjects should be asked for signs and symptoms suggestive of 
an immune-related event. Subjects who develop an ECI thought to be immune-related should 
have additional testing to rule out other etiologic causes. If laboratory results or symptoms 
indicate a possible immune-related ECI, then additional testing should be performed to rule out 
other etiologic causes. If no other cause is found, then it is assumed to be immune-related. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences. 
 
8.3.3. 
Follow-up of AEs, ECIs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs, and ECIs (as defined in Section 10.3.3), will be followed 
until resolution, stabilization, the event is otherwise explained, or the subject is lost to follow-up 
(as defined in Section 7.3). Further information on follow-up procedures is given in Appendix 3. 

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8.3.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the Sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the 
safety of a study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and forwarded to 
investigators as necessary. 
• An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor- 
investigator will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements. 
• Any serious adverse event, or follow up to a serious adverse event, including death 
due to any cause whether or not related to the study drug, must be submitted on an 
SAE form and assessed by PI in order to determine reporting criteria to regulatory 
authorities, IRB, PMC, FDA. Information about all SAEs is collected and recorded 
on the Serious Adverse Event Report Form; all applicable sections of the form must 
be completed in order to provide a clinically thorough report. The investigator (or 
designee; sub-investigator) must assess and record the relationship of each SAE to 
each specific study treatment (if there is more than one study treatment), complete the 
SAE Report Form, and submit the completed form. 
• 
 Each reoccurrence, complication, or progression of the original event should be 
reported as a follow-up to that event regardless of when it occurs. The follow-up 
information should describe whether the event has resolved or continues, if and how 
it was treated, whether the blind was broken or not, and whether the patient continued 
or withdrew from study participation. 
• All SAE must be recorded on a MedWatch 3500 Form. SAE reports and any other 
relevant safety information are to be forwarded as follows, 
MedWatch 3500 Reporting Guidelines: 
Note: MedWatch 3500 forms and other information related to MedWatch 
reporting are available at http://www.fda.gov/medwatch/index.html. 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as 
required by FDA. Investigators will cross reference this submission according to 
local regulations to the Investigational Compound Number (IND, CSA, etc.) at 
the time of submission. 

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• An investigator (or designee; sub-investigator) will evaluate all adverse events 
according to the NCI Common Terminology for Adverse Events (CTCAE), 
version 5.0. Any adverse event which changes CTCAE grade over the course of a 
given episode will have each change of grade recorded on the adverse event case 
report forms/worksheets. All adverse events regardless of CTCAE grade must also 
be evaluated for seriousness. 
• Reporting Requirements for IND holder: 
o For Investigator-sponsored IND studies, reporting requirements for the FDA 
apply in accordance with the guidance set forth in 21 CFR, Part 312.32. 
Events meeting the following criteria need to be submitted to the FDA as 
Expedited IND Safety Reports. 
o 7 Calendar-Day Telephone or Fax Report: 
The Sponsor-Investigator is required to notify the FDA of a fatal or life- 
threatening adverse event that is unexpected and assessed by the investigator 
to be possibly related to the use of investigational agents. An unexpected 
adverse event is one that is not already described in the most recent Guidance 
for Investigator section of the Investigator’s Brochure. Such reports are to be 
telephoned or faxed to the FDA, within 7 calendar days of the first learning of 
the event. 
o 15 Calendar-Day Written Report: 
The Sponsor-Investigator is also required to notify the FDA and all 
participating investigators, in a written IND Safety Report, of any serious 
unexpected adverse event that is considered reasonably or possibly related to 
the use of investigational agent. 
Written IND Safety Reports with analysis of similar events are to be 
submitted to the FDA, within 15 calendar days of first learning of the event. 
The FDA prefers these reports on a MedWatch 3500 Form but alternative 
formats (e.g., summary letter) are acceptable. 
FDA Fax number of IND Safety Reports: 1-(800)-FDA-1078. 
The IND sponsor will also make an assessment of whether the event 
constitutes an unanticipated problem posing risks to subjects or others (UP). 
This assessment will be provided to the IRB, which, in turn will make a final 
determination. If the IRB determines an event is a UP it will notify the 
appropriate regulatory agencies and institutional officials. 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and 
investigators in accordance with all applicable global laws and regulations. 
8.3.5. 
Pregnancy 
• Details of all pregnancies in female subjects and, if indicated, female partners of male 
subjects will be collected after the start of study intervention and until through 5 

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months following cessation of study intervention, or 30 days following cessation of 
study intervention if the subject initiates new anticancer therapy, whichever is earlier. 
• If a pregnancy is reported, the investigator should inform the Sponsor-invstigator 
within 24 hours of learning of the pregnancy and should follow the procedures 
outlined in Appendix 4. 
• Pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of birth, and the presence or absence of any birth 
defects or congenital abnormalities. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
 
8.3.6. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
The following disease related events (DREs) are common in subjects with melanoma and can be 
serious/life threatening: 
• Disease progression; if disease progression occurs, record the date first documented 
in the EOS visit eCRF. Signs and symptoms related to PD should be reported in the 
appropriate eCRF as an AE or as an SAE if the event in question meets the criteria for 
seriousness. 
Because these events are typically associated with the disease under study, they will not be 
reported according to the standard process for expedited reporting of SAEs even though the 
event may meet the definition of a SAE. These events will be recorded on the corresponding 
eCRF page in the subject’s CRF within the appropriate time frame. 
In addition, the following will not be considered AEs 
• Worsening of a pre-existing medical condition, (i.e., diabetes, migraine headaches, 
gout). However, it should be considered an AE if there is either a significant increase 
in severity, frequency, or duration of the condition or an association with significantly 
worse outcomes. 
• Interventions for pretreatment conditions (i.e., elective cosmetic surgery) or medical 
procedures that were planned before study enrollment are not considered AEs. 
NOTE: However, if either of the following conditions applies, then the event must be recorded 
and reported as an SAE (instead of a DRE): 
• The event is, in the Investigator’s opinion, of greater intensity, frequency, or duration 
than expected for the individual subject. 
OR 
• The Investigator considers that there is a reasonable possibility that the event was 
related to study intervention. 

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8.3.7. 
Medical Device Incidents (Including Malfunctions) 
Medical devices are being provided for use in this study for the purposes of electroporation. In 
order to fulfill regulatory reporting obligations worldwide, the investigator is responsible for the 
detection and documentation of events meeting the definitions of incident or malfunction that 
occur during the study with such devices. 
The definition of a Medical Device Incident can be found in Appendix 6. 
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes outlined in 
Section 8.3.3 and Appendix 3 of the protocol. 
 
8.3.7.1. 
Time Period for Detecting Medical Device Incidents 
• Medical device incidents or malfunctions of the device that result in an incident will 
be detected, documented, and reported during all periods of the study in which the 
medical device is used. 
• If the investigator learns of any incident at any time after a subject has been 
discharged from the study, and such incident is considered reasonably related to a 
medical device provided for the study, the investigator will promptly notify the 
Sponsor-invastigator who will notify the study supporter. 
The method of documenting Medical Device Incidents is provided in Appendix 6. 
 
8.3.7.2. 
Follow-up of Medical Device Incidents 
• All medical device incidents involving an AE will be followed and reported in the 
same manner as other AEs (see Section 8.3.3). This applies to all subjects, including 
those who discontinue study intervention. 
• The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the incident. 
• New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator. 
 
8.3.7.3. 
Prompt Reporting of Medical Device Incidents to Study Supporter 
• Medical device incidents will be reported to the Sponsor via email within 24 hours 
after the investigator determines that the event meets the protocol definition of a 
medical device incident. 
• The same individual will be the contact for the receipt of medical device reports and 
SAE. 
 
8.3.7.4. 
Regulatory Reporting Requirements for Medical Device Incidents 
• The investigator will promptly report all incidents occurring with any medical device 
provided for use in the study in order for the Sponsor to fulfill the legal responsibility 
to notify appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies. 

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• The investigator, or responsible person according to local requirements (eg, the head 
of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the IRB/IEC. 
8.4. 
Biomarkers 
• Collection of samples for other biomarker research is also part of this study. Tumor 
biopsies (fixed and fresh) as well as blood and fecal samples will be collected as 
specified in SoA and Appendix 5 (Section 10.5). 
• The main objective of the Immune Monitoring is to characterize the tumor 
microenvironment and assess the immune phenotype and function pre- and post-study 
intervention (tavo-EP in combination with nivolumab) prior to as well as post- 
surgery. 
• Samples may be stored according to local regulations following the last subject’s last 
visit for the study at a facility selected by the Sponsor to enable further analysis. 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
This is a Phase 2 single-agent, open-label study. The primary endpoint of this study is the 
complete pCR at definitive surgery. It is anticipated that combination regimen will improve the 
pCR from an estimated 10% to 30%. 
 
9.2. 
Sample Size Determination 
The statistical power calculations are based on the Simon 2-stage minimax design (Simon, 1989) 
A total of 33 eligible subjects will be enrolled into this study in a 2-stage design. In the first 
stage, up to 22 subjects can be accrued. If there are ≤ 2 responses in these 22 patients, the study 
will be stopped. Otherwise if ≥3 responses are observed, the study will proceed to Stage 2, in 
which an additional 11 subjects will be accrued for a total of 33 subjects. If 7 or more responses 
are observed in 33 subjects, the conclusion will be that the therapy is worthy of further 
investigation. When the true response rate of 30% (alternative hypothesis) is tested against the 
null hypothesis response rate of 10%, this design yields a Type I error rate of 0.05 and power of 
90%. 
9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
 
Population 
Description 
All Subjects as Treated 
(ASaT) / Safety 
All enrolled subjects who received at least 1 dose of either study 
intervention (tavo or nivolumab) 
 
9.4. 
Statistical Analyses 
The statistical analysis plan (SAP) will be developed and finalized before database lock and will 
describe the subject populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints. The SAP may modify the plans outlined in the protocol; 
however, any major modifications will also be reflected in a protocol amendment. 
Since this is an open-label, single arm clinical study, descriptive summary statistics will be 
employed to analyze the data. 
The standard summary statistics for continuous variables are sample size (n), mean, standard 
deviation, median, minimum and maximum. The standard summary statistics for categorical 
variables are frequencies and percentages. Time to event variables will be summarized using the 
Kaplan-Meier method. Where confidence limits are appropriate, the confidence level will be 
95% (two-sided), unless otherwise stated. The only test of statistical significance will be 
performed according to the pre-defined analysis of the Simon 2-stage design. 
Individual data (including relevant derived variables) will be presented by parameter in listings. 
Results of statistical analyses, descriptive summary statistics and supportive listings will also be 
presented. 

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Baseline values are defined as the last valid value prior to study drug administration. Baseline 
safety data will be presented along with subsequent safety values assessed during or after drug 
administration. 
Statistical analyses will be performed using SAS® v9.4 or higher (SAS Institute, Cary NC, 
USA). 
 
9.4.1. 
Subject Disposition 
A detailed description of subject disposition will be provided. It will include: 
• The number of subjects who were included in the safety analysis sets 
• A summary of subjects who complete the protocol 
• A summary of reasons for subject discontinuation 
• A summary of reasons for subject with treatment failure 
• An account of all identified protocol violations 
All subject enrolled in the study will be accounted for in the summation. 
 
9.4.2. 
Demographic and Baseline Characteristics 
Demographic characteristics including age, gender, race, and ethnicity will be presented in the 
form of tabular summary statistics for all ASaT analysis set. Other subject baseline 
characteristics including weight, height, body mass index (BMI), initial stage of disease, and 
performance status will be presented similarly. 
 
9.4.3. 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Primary efficacy analyses will be performed on ASaT Population. 
The pCR will be estimated based on the proportion of subjects with no viable tumor 
on histologic assessment at definitive surgery. The estimated pCR will be 
accompanied by a 2-sided 95% exact binomial confidence interval (CI). Refer to 
statistical analysis plan (SAP) for detail. 
Secondary 
DOR, PFS, iPFS, iBORR and OS (time to events endpoints) will be summarized 
descriptively using Kaplan-Meier methods. The censoring rules will be defined in the 
SAP. The ORR, BORR, and iBORR (categorical endpoints) will be summarized in a 
similar fashion as pCR. These will be assessed by Investigator based on Response 
Evaluation Criteria In Solid Tumors (RECIST) v1.1 at 12 weeks of Neoadjuvant 
phase (preoperative, unconfirmed). Refer to SAP for detail. Further, the risk of 
surgical delay (either due to toxicity and/or tumor progression) will be assessed. 
Surgery will be planned at about 12 weeks and any delays beyond the protocol 
allowed window will be monitored and reported. 

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9.4.4. 
Safety Analyses 
The safety assessment will be based on the frequency of AEs, on the observation of clinically 
significant abnormalities of laboratory values, concomitant medication use, vital signs, pain 
assessment, and physical examination data in the ASaT/Safety analysis set. 
Adverse events: Overall AE as well as AE classified by system organ class and preferred 
terminology will be summarized. Additionally, AE will be summarized by severity and relation 
to study intervention. SAEs and AEs leading to discontinuation will also be tabulated. 
Other safety data: These data will be summarized by presenting the proportions of subjects with 
clinically significant abnormalities or changes from baseline values. Laboratory data will be 
presented in data listings and summarized. 
The following laboratory abnormalities should be captured on the nonserious AE CRF page or 
SAE Report Form (paper or electronic) as appropriate: 
• Any laboratory test result that is clinically significant or meets the definition of an SAE 
• Any laboratory abnormality that required the subject to have study drug discontinued or 
interrupted 
• Any laboratory abnormality that required the subject to receive specific corrective therapy 
 
 
9.4.5. 
Other Analyses 
Immune monitoring exploratory analysis will be described in the SAP finalized before database 
lock. 
9.5. 
Interim Analyses 
No formal interim analyses are planned for this study. Because a Simon 2-stage minimax design 
will be employed, response rate data will be assessed at Stage 1 to determine whether enrollment 
should proceed to Stage 2 per the defined stopping rules. 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− Applicable ICH Good Clinical Practice (GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects. 
• The investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
10.1.2. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
subject or his/her legally authorized representative and answer all questions regarding 
the study. 
• Subjects must be informed that their participation is voluntary. Subjects or their 
legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center. 

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• The research record must include a statement that written informed consent was 
obtained before the subject was enrolled in the study and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign 
the ICF. 
• Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study if required by sponsor-investigator or IRB. 
• A copy of the ICF(s) must be provided to the subject or the subject’s legally 
authorized representative. 
Subjects who are rescreened are required to sign a new ICF. 
 
10.1.3. 
Data Protection 
• The subject must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the subject. 
• The subject must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.4. 
Dissemination of Clinical Study Data 
A clinical study report will be developed by the Sponsor-investigator at completion of data 
analysis. This report will be a clinical and statistical integrated report, according to the ICH E3 
guidelines. 
Sponsor will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations. 
 
10.1.5. 
Data and Safety Monitoring 
Regulatory documents and case report forms will be monitored internally according to Moffitt 
Cancer Center Monitoring Policies. Monitoring will be performed regularly by the MCC Clinical 
Monitoring Core for accuracy, completeness, and source verification of data entry, validation of 
appropriate informed consent process, reporting of SAEs, and adherence to the protocol, Good 
Clinical Practice (GCP) guidelines, and applicable regulatory requirements. 
10.1.6. 
Data Quality Assurance 
• All subject data relating to the study will be recorded on printed or electronic CRF 
(eg, OnCore). 
• The Sponsor must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• The Sponsor must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 

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• The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator per ICH-GCP and local regulations or 
institutional policies. No records may be destroyed during the retention period 
without the written approval of the Sponsor. No records may be transferred to another 
location or party without written notification to the Study Supporter. 
• Study documents should be retained for a minimum of 10 years after the last approval 
of a marketing application in an International Conference on Harmonisation (ICH) 
region and until there are no pending or contemplated marketing applications in an 
ICH region or until at least 10 years have elapsed since the formal discontinuation of 
clinical development of the study intervention. These documents should be retained 
for a longer period, however, if required by local regulations. No records will be 
destroyed without the written consent of the sponsor, if applicable. It is the 
responsibility of the sponsor to inform the investigator when there is no longer a need 
for these documents to be retained. Permission must be acquired from the State of 
Florida for document destruction after the 10-year minimum record-retention period 
described above has elapsed. 
 
10.1.7. 
Source Documents 
• Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s 
site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Source documents are original documents, data, and records from which the subject’s 
eCRF data are obtained. These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
10.1.8. 
Study and Site Closure 
The Study Supporter reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Study Supporter. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 

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Reasons for the early closure of a study site by the Study Supporter or Investigator may include 
but are not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of subjects by the investigator 
• Discontinuation of further study intervention development 
10.1.9. 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the investigator agrees to submit all manuscripts or abstracts to the Study 
Supporter before submission. This allows the Sponsor to protect proprietary 
information and to provide comments. 
• The Sponsor-investigator will comply with the requirements for publication of study 
results. In accordance with standard editorial and ethical practice, the Study Supporter 
will generally support publication only in their entirety and not as individual site data. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 
 
10.1.10. 
Confidentiality and Privacy 
Each participating site will maintain appropriate medical and research records for this 
trial, in compliance with ICH GCP and regulatory and institutional requirements for the 
protection of confidentiality of participants. 

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10.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 4 will be performed as indicated in the study calendar 
(SoA). 
• Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5 of the protocol. 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
Table 4: 
Protocol-Required Safety Laboratory Assessments 
 
Hematology 
White blood cell count (WBC) with 
differential (Neutrophils, Lymphocytes, 
Monocytes, Eosinophils, Basophils) 
Red blood cell (RBC) 
RBC Indices: 
MCV, MCH 
Hemoglobin 
Hematocrit 
Platelet count 
Coagulation factors, including PT or INR and aPTT 
(Screening only if deemed clinically indicated) 
Clinical Chemistriesa 
Alanine Aminotransferase (ALT) 
Aspartate Aminotransferase (AST) 
Alkaline phosphatase 
Albumin 
Total bilirubin (fractionated) 
Blood urea nitrogen (BUN) 
Calcium 
Creatinine 
Sodium 
Magnesium 
Potassium 
CO2 or bicarbonate 
Chloride 
Lactate dehydrogenase (LDH) 
Glucose (non-fasting) 
Total protein 
Phosphates 
Urinalysis 
Basic Urinalysis (dipstick, including 
macroscopic 
appearance, bilirubin, blood, color, glucose, 
ketones, leukocyte esterase, nitrite, pH, 
protein, specific gravity, urobilinogen; prior to 
each administration of study intervention 
treatment). 
Urinalysis includes dipstick and microscopic 
examinations when findings are abnormal 
Other Laboratory Assessments 
Prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR) 
Human chorionic gonadotropin (hCG) pregnancy test as needed for women of childbearing potentiala 
HIV 1/2 antibodies, HBsAg, HCV RNA (qualitative)b 
Thyroid function: free T3, FT4 and thyroid 
stimulating hormone (TSH) 
a For female subjects of child-bearing potential, local urine test must be performed within 72 hours prior to first 
dose of study intervention and if positive, a serum test is required. Similarly, at EOS urine pregnancy test will be 
performed locally and if positive, a serum test is required . 
b Polymerase chain reaction is required and must be negative for HCV RNA in subjects positive for HCV antibody 

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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a subject or clinical study subject, temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of study intervention. 
 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the Investigator (i.e., not related to progression of underlying disease). 
• 
Worsening of a pre-existing medical condition, (i.e., diabetes, migraine headaches, gout) 
should be considered an AE if there is either an increase in severity, frequency, or duration of 
the condition or an association with significantly worse outcomes. 
• 
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is 
an intentional overdose taken with possible suicidal/self-harming intent. Such overdoses 
should be reported regardless of sequelae. 
 
 
Events NOT Meeting the AE Definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the Investigator to be more 
severe than expected for the subject’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 

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10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
 
A SAE is defined as any untoward medical occurrence that, at any dose: 
1. Results in death 
2. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was 
at risk of death at the time of the event. It does not refer to an event, which hypothetically might 
have caused death, if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting. Complications that occur 
during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or 
was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
4. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
5. Is a congenital anomaly/birth defect 
6. Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse. 
 
10.3.3. 
Definition of Events of Clinical Interest 
Events of Clinical Interest for tavo-EP are by the Sponsor defined as: 
• 
Immune-related ECIs are AEs of unknown etiology, associated with drug exposure and is 
consistent with an immune phenomenon 

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10.3.4. 
Definition of Suspected and Unsuspected Adverse Reaction 
Suspected adverse reactions are defined as: 
• 
Any AE for which there is a reasonable possibility that the study intervention caused the 
AE. For the purposes of Sponsor regulatory safety reporting, “reasonable possibility” means 
there is evidence to suggest a causal relationship between the study intervention and the AE. 
A suspected adverse reaction implies a lesser degree of certainty about causality than 
adverse reaction, which means any AE caused by a study intervention 
Unexpected Adverse events are defined as: 
• 
AE which is not listed in the IB of the study intervention or is not listed at the specificity or 
severity that has been observed 
 
 
10.3.5. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the Investigator to send photocopies of the subject’s medical records 
to the principal investigator in lieu of completion of the AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by the 
principal investigator. In this case, all subject identifiers, with the exception of the subject 
number, will be redacted on the copies of the medical records before submission to the 
principal investigator. 
• 
An overdose of study intervention, that is not associated with clinical symptoms or 
abnormal laboratory results 
• 
An elevated AST or ALT laboratory value that is greater than or equal to 3 × ULN and an 
elevated total bilirubin lab value that is greater than or equal to 2 × ULN and, at the same 
time, an alkaline phosphatase laboratory value that is less than 2 × ULN, as determined by 
way of protocol-specified laboratory testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. The study site guidance for assessment and follow up of 
these criteria can be found in the Investigator Trial File Binder (or equivalent). 
• 
Tissue ulceration or cellulitis infections related to Tavo injection and/or EP. 
• 
Delay in definitive surgery beyond the protocol allowed windows. 

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AE and SAE Recording 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
AE severity will be evaluated by the Investigator in accordance with the NCI CTCAE v5.0. For 
AEs that are not adequately addressed in the NCI CTCAE, the Investigator should classify the 
intensity of the AE using the following guidelines: 
• 
Grade 1: Mild: Aware of sign or symptom, but easily tolerated; no intervention needed 
• 
Grade 2: Moderate: Discomfort enough to cause interference with usual activity, 
minimal non-invasive intervention indicated (e.g., short course of antibiotics) 
• 
Grade 3: Severe: Medically significant but not immediately life-threatening; 
incapacitation with inability to work or do usual activity 
• 
Grade 4: Life-threatening: Refers to an event in which the subject was at risk of death at 
the time of the event, as judged by the Investigator; urgent/emergent intervention 
indicated. This category should not be used for an event that hypothetically might have 
caused death if it were more severe. 
• 
Grade 5: Fatal outcome. 
It will be left to the Investigator’s clinical judgment to determine whether an AE is of 
sufficient severity to require the subject’s removal from treatment or from the study. A 
subject may also voluntarily withdraw consent from treatment due to what she/he 
perceives as an intolerable AE. If either of these situations arises, the subject should be 
strongly encouraged to undergo an end-of-study assessment and be under medical 
supervision until symptoms cease or the condition becomes stable. An event is defined as 
‘serious’ when it meets at least 1 of the predefined outcomes as described in the 
definition of an SAE, NOT when it is rated as severe. 
 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE as follows: 
CAUSALITY 
ASSESSMENT CRITERIA 
(all points should be reasonably complied with) 
Not related 
An AE with sufficient evidence to accept that there is improbable 
relationship to investigational product administration (e.g., no 
temporal relationship to drug administration) and the disease, other 
drugs or other events provide plausible explanation) 
Possibly 
related 
An AE with a reasonable time sequence to administration of the 
investigational product, but which could also be explained by 
concurrent disease or other drugs or events. Information on drug 
withdrawal may be lacking or unclear 

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Assessment of Causality 
Related 
An AE occurring in a plausible time relationship to investigational 
product administration, and which cannot be explained by a 
concurrent disease or other drugs or events. The response to 
withdrawal of the drug (de-challenge) and rechallenge (if necessary), 
are clinically reasonable 
• 
A “"reasonable possibility”" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration will be 
considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to principal investigator. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to principal investigator. 
• 
The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
 
Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by principal 
investigator to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
 
10.3.6. 
Reporting of SAEs 
SAE Reporting to Study Supportervia an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to Study Supporter will be the electronic data 
collection tool (i.e., MedWatch 3500 form or Oncore SAE form) in accordance with Moffitt 

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SAE Reporting to Study Supportervia an Electronic Data Collection Tool 
Cancer Center local regulations. The site will enter the SAE data into the electronic system 
as soon as it becomes available. 
• 
After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study subject or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, 
then the site can report this information on a paper SAE form (see next section) or to the 
principal investigator by telephone. 
• 
OncoSec Contacts for SAE reporting: 
Oncosec Medical Representative: 
Terrence Chew, MD 
Email: safety@oncosec.com 

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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the subject’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
− A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than one FSH measurement 
is required. 
• Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
 
Contraception Guidance: 
Acceptable methods include hormonal contraception (oral contraceptives – as long as on stable 
dose, patch, implant, and injection), intrauterine devices, or double barrier methods (e.g. vaginal 
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a vasectomized partner. Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
 
Collection of Pregnancy Information 
 
Male subjects with partners who become pregnant 
• The investigator will attempt to collect pregnancy information on any male subject’s 
female partner who becomes pregnant while the male subject is in this study. 
• After obtaining the necessary signed ICF from the pregnant female partner directly, 
the investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor-investigator within 24 hours of learning of the partner’s 
pregnancy. The Sponsor will attempt to follow the female partner to determine the 
outcome of the pregnancy. Information on the status of the mother and child will be 
forwarded to the Sponsor. The Sponsor will follow the female partner until birth or 
termination of pregnancy when possible. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for 
the procedure. 
 
Female Subjects who become pregnant 
• The investigator will collect pregnancy information on any female subject who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the Sponsor within 24 hours of learning of a 
subject's pregnancy. 
• The subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the subject and the neonate and the 
information will be forwarded to the Sponsor. The subject will be followed until birth 
or termination of pregnancy. Any termination of pregnancy will be reported, 
regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported 
as such. Any post-study pregnancy related SAE considered reasonably related to the 
study intervention by the investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this information 
in former study subjects, he or she may learn of an SAE through spontaneous 
reporting. 
• Any female subject who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 

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10.5: Collection of Human Samples for Immune Monitoring 
Immune Monitoring tumor biopsies (fixed and fresh) as well as blood and fecal samples will be 
collected during this study to characterize the tumor microenvironment and to assess the immune 
phenotype and function pre- and post-combination therapy of tavo-EP and nivolumab. 
Eligible subjects at all participating sites will take part in this immune monitoring. Fresh tumor 
biopsies will be collected at North America sites only. Biopsies should not proceed if (a) tumor 
is inaccessible or (b) biopsy is not thought to be in the subject’s best interest, (c) the tumor is a 
target lesion and the biopsy is being collected between C1D1 and definitive surgery, or (d) non- 
target lesion (unless there is no change in LD and >15% of tumor volume). Biopsies do not need 
to be done if either the site investigator or person performing the biopsy judges that no tumor is 
accessible for biopsy that meet the size/volume requirements or that biopsy poses too great of a 
risk to the subject and will not be noted as a deviation. (If the only tumor accessible for biopsy is 
also the only lesion that can be used for RECIST v1.1 response evaluation, then the subject may 
be exempt from biopsy after discussion with the principal investigator and no deviation is 
documented). Other minor deviations will be recorded for subjects with procedures not done. 
The samples will be collected during the study as specified in the SoA and shipped to the central 
laboratory, for storage, or to OncoSec or third-party vendors for analyses (including but not 
limited to immune-based assays, protein biomarkers and gene expression profiling, and RNA- 
seq). 
Sample collection methods and handling at the study site are described below for each type of 
sample. 
Tumor Biopsies 
In addition to fixed biopsies, fresh biopsies are to be collected as specified in the SoA. Thus two 
tumor biopsies will be acquired from any accessible treated RECIST v1.1 measurable or 
non-target lesions >10 mm and/or untreated cutaneous lesions >5 mm. These biopsies will be 
placed into a shipping media (“fresh”) and fixed in 10% formalin. Possible use include but is not 
limited to the following: Assess PD-L1 and immune marker levels in the tumor 
microenvironment (tumor, stroma and immune infiltrate) by chromogenic and multispectral 
immunohistochemistry (IHC) workflows. DNA and RNA may also be extracted from these fixed 
tumor biopsies and used to interrogate intratumoral gene expression by NanoString, RNA-seq 
analysis as well as epigenetic analysis with an Illumina Methylation Array workflow. The DNA 
from the biopsy may be used to detect levels of pIL-12 by qPCR, changes in clonality or antigen- 
specific TCR sequences with an Adaptive Biotechnologies analysis and the potential mutation 
load and neo-antigen repertoire in the tumor by whole exome sequencing. The fresh biopsy may 
be used in a flow cytometric assay to determine the frequency of PD-1hiCTLA-4hi cells in the 
live CD45+CD3+CD8+ gate (Daud, 2016) or to establish and culture tumor and TIL lines that 
may be used in functional immune assays. 
If reasonable for subject therapy, at least 1 distal, non-target lesion shall be left untreated with 
biopsies taken at timepoints before and after treatment as described above. If only one biopsy is 
possible, the sample should be a fixed biopsy. For collection of tumor biopsies, the lesion should 
be accessible and of an appropriate size. The biopsy should be done under sterile conditions with 
adequate tissue to be collected: one 5 mm punch, core, or excisional biopsy. Prior to biopsy 

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Collection and if considered clinically indicated, coagulation assessment will be done 
including prothrombin time (PT), partial thromboplastin time (PTT), and international 
normalized ratio (INR). 
Handling instructions for tissue biopsy are as follows: 
Fixed Biopsy: A Fixed Tumor Biopsy Collection Kit should be used at all study time points for 
the collection of fixed tumor samples. Place the tumor tissue sample in the formalin container 
and close the cap tightly. After 12-24 hours, the tissue shall be placed in PBS (+ 0.01% azide) 
and stored at ambient temperatures until shipment. 
Fresh Biopsy: Insert the fresh tissue sample into a pre-chilled container with XVIVO-15 media 
and immediately place on ice. The sample must remain cold and on ice until ready for overnight 
4°C shipment to the central laboratory. 
 
NOTE: Existing FFPE tumor samples from previous and future (while on study) melanoma tumor 
biopsies should be requested if available and should be submitted for research purposes. Up to 20 
unstained slides may be requested if available. Provision of less than 20 slides is acceptable based 
on availability. This applies primary melanoma tumor lesions and metastatic melanoma tumor 
lesions. These should be requested in addition to the protocol indicated research biopsies.  

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Blood Sampling 
Blood collected from the subject as outlined in the SoA may be used to evaluate changes in the 
subject’s peripheral immune cells and circulating levels of pIL-12 by qPCR. Peripheral blood 
mononuclear cells (PBMC) isolated with BD’s CPT tube (see details below) may be used in flow 
cytometric and ELISpot workflows to interrogate immune phenotype, tetramer frequencies and 
immune function. Blood will be collected for serum isolation and analysis of protein signatures. 
Please refer to ‘Human Sampling for Immune Monitoring manual’ for details on blood sampling 
collection. Briefly, blood sampling will be collected for immuno-assays at the same time of 
blood chemistry collections as follows: 
1. One 2.5 mL PAXgene™ RNA Vacutainer Tube 
2. One 2.5 mL PAXgene™ DNA Blood Collection Tube 
3. Nine 8.0 mL Vacutainer CPT Tubes 
Handling for item 3 above: the CPT Tube should be at room temperature (18-25°C) and 
centrifuged within two hours of blood collection for best results. The cells in the upper phase 
(the plasma above the gel barrier) are to be re-suspended by inverting the unopened CPT tube 
gently 5 to 10 times before proceeding with shipment of processed blood at 4°C. Samples should 
be shipped same day as collection. 
4. One 3.0 mL Vacutainer Serum Tube, Increased Silica Act Clot Activator 
Handling instructions for item 4 above: Allow for the blood to clot by leaving it undisturbed at 
room temperature for 30 minutes. Remove the clot by centrifuging at 1,300 x g for 10 minutes in 
a centrifuge. Serum will be aliquoted and frozen, then shipped (if necessary) frozen where they 
will be stored at -80C. Samples should be shipped same day as collection. 
Fecal Sampling 
Approximately 2 grams of fecal matter will be collected by the subject using Norgen Biotek’s 
Stool Nucleic Acid Collection and Transport tubes. If the subject cannot provide this sample at 
the clinical site, a kit will be provided to go home with the subject. Samples can be stored at 
room temperature up to 72 hours until ambient shipment to the laboratory where they will be 

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stored at -80°C. These samples will subsequently be used for 16S rDNA and/or metagenome 
sequencing, allowing for the elucidation of microbial composition and genome structure. 
Subjects will be instructed to: 
Avoid any contact between the stool sample and urine. 
• Pass stool directly onto the provided plastic wrap (if stool is loose, subjects will use a 
provided large clean container) placed under the seat of the toilet. 
• Scoop stool sample from three sites using the spoon attached in the cap and place the 
stool into the tube until the liquid reaches the “Fill To This Line” (Do not over fill). 
• Tighten the cap and shake gently until the stool is thoroughly mixed with the 
preservative before returning the tube to the clinician or placing the tube in the 
shipping envelope. 
• Samples collected at home will be stored in a sealed shipping envelope at room 
temperature for up to 72 hours, while the courier service will be notified for next day 
pickup. 

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10.6. 
Appendix 6: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definitions of a Medical Device Incident 
The detection and documentation procedures described in this protocol apply to all Sponsor 
medical devices provided for use in the study (see Section 6.1.1 ) for the list of Sponsor medical 
devices). 
 
Medical Device Incident Definition 
• 
A medical device incident is any malfunction or deterioration in the characteristics and/or 
performance of a device as well as any inadequacy in the labeling or the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a 
subject/user/other person or to a serious deterioration in his/her state of health. 
• 
Not all incidents lead to death or serious deterioration in health. The nonoccurrence of such a 
result might have been due to other fortunate circumstances or to the intervention of health 
care personnel. 
It is sufficient that: 
• An incident associated with a device happened. 
 
AND 
 
• The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health. 
A serious deterioration in state of health can include any of the following: 
• Life-threatening illness 
• Permanent impairment of body function or permanent damage to body structure 
• Condition necessitating medical or surgical intervention to prevent one of the above 
• Fetal distress, fetal death, or any congenital abnormality or birth defects 
 
Examples of Incidents 
• 
A subject, user, caregiver, or healthcare professional is injured as a result of a medical device 
failure or its misuse. 
• 
A subject’s study intervention is interrupted or compromised by a medical device failure. 
• 
A misdiagnosis due to medical device failure leads to inappropriate treatment. 
• 
A subject’s health deteriorates due to medical device failure. 

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Documenting Medical Device Incidents 
Medical Device Incident Documenting 
• 
Any medical device incident occurring during the study will be documented in the subject’s 
medical records, in accordance with the investigator’s normal clinical practice, and on the 
appropriate form of the eCRF. 
• 
For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE CRF page 
will be completed as described in Appendix 3. 
• 
The eCRF will be completed as thoroughly as possible and signed by the investigator before 
transmittal to the Sponsor or designee. 
• 
It is very important that the investigator provides his/her assessment of causality (relationship 
to the medical device provided by the Sponsor) at the time of the initial AE or SAE report and 
describes any corrective or remedial actions taken to prevent recurrence of the incident. 
• 
A remedial action is any action other than routine maintenance or servicing of a medical device 
where such action is necessary to prevent recurrence of an incident. This includes any 
amendment to the device design to prevent recurrence. 

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10.7. 
Summary of Response Evaluation Criteria for Solid Tumors 
(RECIST) and Immune RECIST (iRECIST) 
 
 
 
NOTE: Response evaluation by RECIST is required per 
protocol and it is optional by iRECIST. 
 
10.7.1. 
RECIST v1.1 
Tumor response will be evaluated according to RECIST guidelines (Therasse, 2000) using tumor 
imaging (see Section 10.7.3 for tumor imaging details). 
Assessment by RECIST v1.1 will be done as specified in the SoA. If during the neoadjuvant 
phase, a treatment delay results in shifting cycles, imaging and tumor evaluation will be shifted 
accordingly. Lesions will be numbered identically for each visit as Target and non-target, new 
lesions (see definitions in Table 8). 
In support of RECIST v1.1, when more than one accessible and measurable tumor is present at 
baseline, all lesions (those with the longest diameter(s)/ organ that are measurable in the 
physicians’ discretion) up to 2 cutaneous lesions assessed by photography and up to 5 visceral or 
subcutaneous lesions (2 per organ), assessed by radiology, with a maximum of 7 lesions total 
should be identified as measurable representative Target Lesions. A target lesion may be a 
treated or untreated lesion. 
An ‘accessible lesion’ is defined as a cutaneous or subcutaneous lesion that can be reached from 
the surface with the electroporation needle array (with depth of up to 1.5 cm from the surface). 
Measurable lesions include non-lymph node longest axis ≥10 mm (on CT, PET-CT, MRI, or 
calipers/rulers), non-lymph node longest axis ≥20 mm (on X-ray) and lymph node short axis 
≥15 mm. All lesions will be indicated by pen and numbered before being photographed. This 
provides the baseline map of ALL accessible lesions with baseline defined as the period between 
signing the ICF and prior to completion of Cycle 1. Each lesion will be identified by a lesion 
number which must remain the same throughout the study. Measurable lesions that are target 
lesions must be measured by the site and data entered into electronic data capture (EDC). 
Each subject will be assigned a response category (Table 5): complete response (CR), partial 
response (PR), stable disease (SD), progressive disease (PD). 
Preoperative response rate (unconfirmed) will be assessed during the Neoadjuvant phase 
(preoperative, unconfirmed). 

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Table 5 
Response Evaluation Criteria in Solid Tumors v1.1 
 
RECIST v1.1 Response 
Criteria 
Target Lesions 
Non-Target Lesions 
Complete Response (CR)1 
Disappearance of all target 
lesions, determined by two 
separate observations conducted 
not less than 4 weeks apart. Any 
pathological lymph nodes 
(whether target or non-target) 
must have reduction in short 
axis to <10 mm (the sum may 
not be “0” if there are target 
nodes). There can be no 
appearance of new lesions. 
Disappearance of all non-target 
lesions and normalization of 
tumor marker level. All lymph 
nodes must be non-pathological 
in size (<10 mm short axis). 
Partial Response (PR)1 
At least a 30% decrease in the 
sum of the longest diameter 
(LD) of target lesions, taking as 
reference the baseline sum LD. 
There can be no appearance of 
new lesions. 
Non-target lesions must be 
non-PD. 
Stable Disease (SD) 
Neither sufficient shrinkage to 
qualify for PR nor sufficient 
increase to qualify for PD, 
taking as reference the smallest 
sum LD since the treatment 
started. 
Persistence of one or more 
non-target lesion(s) and/or 
maintenance of tumor marker 
level above the normal limits. 
Progressive Disease (PD) 
At least a 20% increase in the 
sum of diameters of measured 
lesions taking as references the 
smallest sum of diameters 
recorded on study (including 
baseline) AND an absolute 
increase of ≥5 mm, or the 
appearance of one or more new 
lesions. 
Appearance of one or more new 
lesions and/or unequivocal 
progression of existing 
non-target lesions. 
 
 
 
 
 
 
1 Subjects will meet the primary endpoint (BORR) if they attain a confirmed CR or PR over the 24 weeks with the 
combination treatment with a 4-week confirmatory scan per RECIST v1.1. 

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10.7.1.1. Evaluation of Overall Response with RECIST v1.1 
The overall response recorded from the start of the treatment until disease progression/recurrence 
(taking as reference for progressive disease the smallest measurements recorded since the 
treatment started). The subject's best response assignment will depend on the achievement of 
both measurement and confirmation criteria (Table 6). 
Table 6 
Overall Response Definitions using RECIST v1.1 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this Category 
Also Requires 
CR 
CR 
No 
CR 
Normalization of tumor markers, 
tumor nodes <10 mm 
CR 
Non-CR/ Non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD / No all 
evaluated 
No 
PR 
SD 
Non-PD 
No 
SD 
Documented at least once 
≥4 weeks from baseline 
Not all 
evaluated 
Non-PD 
No 
NE 
PD 
Any 
Any 
PD 
Any 
PD* 
Any 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression  in non-target lesions may  be accepted as disease 
progression 
Source: (Seymour, 2017) 
Other definitions 
• 
Duration of response (DOR) 
• 
Relapse free survival (RFS) – RFS is defined as the time, in months, from the first dosing date until the 
date of disease relapse (i.e., the date of the tumor imaging) or death from any cause. RECIST v1.1 will 
be used to determine the dates of relapse as this methodology is accepted by regulatory authorities. 
This will be further detailed in the SAP. 
• 
Overall survival (OS) - OS is defined as the time from diagnosis until death from any cause. 
Subjects without a confirmed date of death will be censored at the last date when the 
subject was known to be alive. 
 
10.7.2. 
Immune-Related RECIST (iRECIST) 
iRECIST will be used to assess a secondary endpoint (refer to Section 3) according to recently 
published consensus guidelines for iRECIST (Seymour, 2017). 
Assessment by iRECIST will be done at 12-week intervals as specified in the SoA. Lesions will 
be numbered identically for each visit as Target and non-target, new lesions (see definitions in 
Table 8). 

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Immunotherapeutics may result in infiltration of immune cells leading to transient increase in the 
size in malignant lesions, or undetectable lesions becoming detectable. The criteria are identical 
to those of RECIST v1.1 in many respects but have been adapted to account for instances where 
an increase in tumor burden, or the appearance of new lesions, does not reflect true tumor 
progression. 
Unlike RECIST v1.1, iRECIST requires the confirmation of progression and uses the terms 
iUPD (immune unconfirmed progression) and iCPD (immune confirmed progression). 
For target lesions, iCR, iPR, and iSD can all be assigned after iUPD has been documented, if 
iCPD was not confirmed (Table 7). iUPD is defined by RECIST v1.1 criteria for progressive 
disease; iUPD can be assigned multiple times as long as iCPD is not confirmed at the next 
assessment. Progression is confirmed in the target lesion category if the next imaging assessment 
after iUPD (4–8 weeks later) confirms a further increase in sum of measures of target disease 
from iUPD, with an increase of at least 5 mm. However, the criteria for iCPD (after iUPD) are 
not considered to have been met if CR, PR, or SD criteria (compared with baseline and as 
defined by RECIST v1.1) are met at the next assessment after iUPD. The status is reset (unlike 
RECIST v1.1, in which any progression precludes later CR, PR, or SD). iCR, iPR, or iSD should 
then be assigned; and if no change is detected, then the timepoint response is iUPD. 
The assessment of non-target lesions at each timepoint follows similar principles. iUPD (but not 
iCPD) can have been documented before iCR or when the criteria for neither CR nor PD have 
been met (referred to as non-iCPD/non-iUPD) and can be assigned several times, as long as 
iCPD was not confirmed. iUPD is defined by RECIST v1.1 criteria; however, iUPD can be 
assigned multiple times as long as iCPD is not confirmed at the next assessment. Progressive 
disease in the non-target lesion category is confirmed if subsequent imaging, done 4–8 weeks 
after iUPD, shows a further increase from iUPD. The criteria for iCPD are not judged to have 
been met if RECIST v1.1 criteria for complete response or non-iCR/non-iUPD are met after a 
previous iUPD. The status is reset (unlike RECIST v1.1) and iCR, or non-iCR/non-iUPD is 
assigned; if no change is detected, the timepoint response is iUPD. 
iCPD is confirmed if further increase in tumor burden, compared to the last assessment, is seen as 
evidenced by one or more of the following: 
• 
Continued increase in tumor burden (from iUPD) where RECIST v1.1 definitions of 
progression had been met (from nadir) in target, non-target disease or new lesions 
− 
Progression in target disease worsens with an increase of at least 5 mm in the absolute 
value of the sum 
− 
Continued unequivocal progression in non-target disease with an increase in tumor 
burden 
− 
Increase in size of previously identified new lesion (s) (an increase of at least 5 mm 
in the absolute value of the sum of those considered to be target new lesions) or 
additional new lesions. 
• 
RECIST v1.1 criteria are met in lesions types (target or non-target or new lesions) where 
progression was not previously identified, including the appearance of additional new 
lesions. 

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If iUPD is not confirmed at the next assessment, then the appropriate response will be assigned 
(iUPD if the criteria are still met, but no worsening, or iSD, iPR or iCR if those criteria are met 
compared to baseline). The prior documentation of iUPD does not preclude assigning iCR, iPR, 
or iSD in subsequent time-point assessments or as immune best overall response (iBORR) 
providing that iCPD is not documented at the next assessment after iUPD. 
The event date to be used for calculation of progression-free survival (iPFS) should be the first 
date at which progression criteria are met (i.e., the date of iUPD) provided that iCPD is 
confirmed at the next assessment. If iUPD occurs, but is disregarded because of later iSD, iPR, 
or iCR, that iUPD date should not be used as the progression event date 
Table 7 
iRECIST Time Point response 
 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
Time Point Response 
No 
prior 
iUPD** 
Prior iUPD**; *** 
iCR 
iCR 
No 
iCR 
iCR 
iCR 
Non-iCR/Non-iUPD 
No 
iPR 
iPR 
iPR 
Non-iCR/Non-iUPD 
No 
iPR 
iPR 
iSD 
Non-iCR/Non-iUPD 
No 
iSD 
iSD 
iUPD with no 
change OR 
decrease from 
last time point 
iUPD with no 
change OR decrease 
from last TP 
Yes 
NA 
New lesions (NL) confirms iCPD if NLs were 
previously identified and increase in size (≥5 mm 
in sum of measure (SOM) for new lesion, target 
(NLT) or any increase for new lesion, non-target; 
NLNT) or number. If no change in NLs (size or 
number) from last time point, remains iUPD 
iSD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based in 
further increase in size of non-target disease (need 
not meet RECIST v1.1 criteria for unequivocal 
PD) 
iUPD 
Non-iCR/Non-iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on: 
o further increase in SOM of at least 5 mm, 
otherwise remains iUPD 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on 
further increase in: 
o previously identified T lesion iUPD sum of 
measure ≥5 mm and / or 
o NT lesion iUPD (prior assessment - need not be 
unequivocal PD) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on 
further increase in: 
• 
previously 
identified 
Target 
lesion iUPD ≥5 mm and / or 
• 
previously identified non-target 
lesion iUPD (need not be 
unequivocal) and /or 
• 
size or number of new lesions 
previously identified 
Non-iUPD/PD 
Non-iUPD/PD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on 

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o increase in size or number of new lesions 
previously identified 
TP = time-point; NT = non-target, T = target; NL = new lesions; iUPD = unconfirmed immune PD; iCPD = 
confirmed immune PD; SOM = sum of measures. iCR – immune complete response; iPR – immune partial 
response; iSD – immune stable disease 
* Using RECIST v1.1 principles. If no PSPD occurs, RECIST v1.1 and iRECIST categories for CR, PR and SD 
would be the same. 
** in any lesion category. 
*** previously identified in assessment immediately prior to this time point. 
Source: (Seymour, 2017) 
 
10.7.3. 
Measurable Disease and Lesions Definitions 
Table 8 provides definitions for measurable disease and lesions, target and non-target lesions. At 
all study visits, each lesion will always be assessed with the same method. 
Table 8 
Definitions of Measurable Disease and Lesions 
 
Parameter 
Definitions 
Measurable 
disease 
Measurable tumor lesions (nodal, subcutaneous, lung parenchyma, solid organ 
metastases) are defined as those that can be accurately measured in at least one 
dimension (longest diameter [LD] to be recorded) as ≥20 mm with chest x-ray and 
as ≥10 mm with CT scan or clinical examination. Bone lesions are considered 
measurable only if assessed by CT scan and have an identifiable soft tissue 
component that meets these requirements (soft tissue component ≥10 mm by CT 
scan). Malignant lymph nodes must be ≥15 mm in the short axis to be considered 
measurable; only the short axis will be measured and followed. All tumor 
measurements must be recorded in millimeters (or decimal fractions of 
centimeters). Previously irradiated lesions are not considered measurable unless 
progression has been documented in the lesion. These should be recorded and 
measured prior to treatment at Cycle 1 Day 1 (C1D1; baseline). 
Non-measurable 
disease 
All other lesions (or sites of disease), including small lesions are considered 
non-measurable disease. Bone lesions without a measurable soft tissue 
component, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, lymphangitic 
involvement of lung or skin and abdominal masses followed by clinical 
examination are all non-measurable. Lesions in previously irradiated areas are 
non-measurable, unless progression has been demonstrated. 
Target lesions 
All measurable lesions up to a maximum of 7 lesions total (and a maximum of 2 
lesions per organ) with 2 cutaneous lesions assessed by photography and up to 5 
visceral or subcutaneous lesions assessed by radiology. Measurable lesions 
should be representative of all involved organs and should be identified as target 
lesions and recorded and measured at baseline. Target lesions will be selected 
based on their size (lesions with the LD) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically). At baseline, the sum 
of the LD for all target lesions will be calculated and reported as the baseline sum 
LD. The baseline sum LD will be used as reference by which to characterize the 

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objective tumor response. After baseline, a value should be provided on the CRF 
for all identified target lesions for each assessment, even if very small. If 
extremely small and faint lesions cannot be accurately measured but are deemed 
to be present, a default value of 5 mm may be used. If lesions are too small to 
measure and indeed are believed to be absent, a default value of 0 mm may be 
used. 
Non-target 
lesions 
All other lesions (or sites of disease) including any measurable lesions over and 
above the 7 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. It is possible to record multiple non-target lesions 
involving the same organ as a single item on the case record form (e.g. “multiple 
enlarged pelvic lymph nodes” or “multiple liver metastases”). Bone lesions may 
be measurable if ≥ 1 cm on MRI. Measurements of these lesions are not required, 
but the presence or absence of each will be noted throughout follow-up. It is 
recommended that bone lesions be followed closely by investigators by 
comments and measurements whenever possible for retrospective review. 
Measurements are not required but these lesions should be noted at baseline and 
should be followed as “present” or “absent”. 
Source: (Seymour, 2017) 
 
10.7.4. 
Tools for Tumor Assessments 
 
10.7.4.1. Tumor Imaging for Evaluation of Response 
Radiographic imaging will be done at frequency specified in SoA. 
Tumor imaging is strongly preferred to be acquired by CT. For the abdomen and pelvis, 
contrast-enhanced MRI may be used when CT with iodinated contrast is contraindicated, or 
when mandated by local practice. MRI is the strongly preferred modality for imaging the brain. 
The same method of assessment and the same imaging technique will be used to characterize 
each identified and reported lesion at baseline and during the study. Ideally the same scanner, 
and the use of contrast should be used in a subject throughout the study to optimize the 
reproducibility of the assessment of existing and new tumor burden and improve the accuracy of 
the assessment of response or progression based on imaging. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 
Note: for the purposes of assessing tumor imaging, the term “investigator” refers to the local 
investigator at the site. 

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10.8. 
Surgical Considerations 
The investigators are expected to make every effort to comply with the surgical procedures 
within the time windows allowed in this study protocol. However, under certain circumstances 
and as discussed between the sub-investigator(s) (both surgeon and medical oncologist) and the 
principle investigator, an alteration in the surgical schedule/timing is allowed. These include (but 
are not limited to) the following: 
• A 4-week window between the baseline biopsy and the first dose of study 
intervention is allowed. 
• The definitive surgery may be a lymphadenectomy, resection of lymphatic metastases 
and/or resection of newly appearing distant oligometastases, as clinically indicated. 
• The definitive surgery may be divided into more than one surgical procedure, 
scheduled at different time points as clinically/surgically indicated. 
• Under certain circumstances, the definitive surgery may be delayed and done after 
completion of additional cycles of neoadjuvant therapy (or earlier if study 
intervention(s) was discontinued due to adverse events or other reasons). 
• If for some reason, the baseline biopsy or definitive surgery could not be completed 
due to un-anticipated factors such as patient refusal, this will be documented in the 
subject medical record and OnCore. 
• For the baseline biopsy required on this study, patients will undergo a standard core 
needle technique (16 gauge or thicker), punch biopsy, open technique, or other 
technique at the discretion of the treating physician investigator(s). The choice of 
specific surgical technique will be at the discretion of the surgeon or medical 
oncologist and actual techniques will be the same as those used as therapeutically or 
diagnostically indicated to surgically treat or confirm the clinical suspicion of 
recurrent or metastatic disease in any patient undergoing conventional evaluation and 
treatment (standard of care) within 4 weeks prior to initiating study drug(s) (baseline 
biopsy). 
NOTE: The surgical guidelines are general and may be followed or modified at the discretion of 
the expert surgical oncologist on the case as clinically indicated and depending on the specifics 
of the individual surgical case. 
 
10.8.1. 
Primary Excision or Primary Cutaneous Melanoma 
All patients with initial presentation of melanoma T1-4 will be treated by wide excision of the 
primary. Definitive surgery will include wide excision of the primary and lymphadenectomy. 
For patients with known primary cutaneous melanoma lesion and no history of wide local 
excision of that primary lesion, an adequate wide excision of the primary lesion (minimum 
margin 1 cm if anatomically feasible) is recommended. The wide local excision will be done at 
the time of complete lymphadenectomy. Patients with nodal relapse after an inadequate primary 
excision will undergo wide excision at the time of complete lymphadenectomy. The 
recommendation for adequate wide excision is the same for patients enrolled at the time of 
lymph node recurrence as for those enrolled at the time of initial treatment of the primary. For 

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lesions whose Breslow's thickness is > 1 mm, a 2 cm minimum margin is preferred when 
anatomically feasible (i.e., for lesions of the trunk and proximal extremities). For subungual 
melanoma, a distal interphalangeal amputation with histologically negative margins constitutes 
an adequate wide excision. The specimen shall be excised to include skin and all subcutaneous 
tissue down to the muscular fascia. Fascia may be included at the discretion of the operating 
surgeon. Closure of the defect may be via primary closure, split thickness skin graft, or rotation- 
flap at the discretion of the surgeon. 
 
10.8.2. 
Regional Lymphadenectomy 
 
10.8.2.1. Head and Neck Lesions 
• Face, ear and anterior scalp: Modified radical neck or radical neck dissection. 
• Submandibular and anterior neck: Modified radical or radical neck dissection. 
• Posterior scalp, posterior neck and uppermost trunk (areas that drain to posterior 
cervical triangle): Modified posterior triangle neck dissection with suboccipital nodes 
(to yield a minimum of 8 nodes). 
10.8.2.2. Upper Extremity 
Axillary node dissection for levels I and II. Level III nodes should be dissected if they are 
clinically involved. The pectoralis minor muscle may be divided or sacrificed at the surgeon's 
discretion. 
 
10.8.2.3. Lower Extremity 
Superficial inguinal node dissection will be performed. A deep inguinal node dissection will be 
at the discretion of the surgeon, but if performed, the established guidelines should be followed 
as closely as possible. 
10.8.2.4. Lymphadenectomy for Nodal Recurrence 
Regional node recurrences will be treated using the appropriate lymphadenectomy procedure. 
Whenever possible, diagnosis of regional node recurrence will be made using punch or open 
biopsy technique (if done as part of a clinically indicated baseline diagnostic procedure) to 
provide baseline pathologic material needed for evaluation of treatment effect. At the time of the 
definitive lymphadenectomy, the biopsy site will be included in the operative specimen. 
10.8.3. 
Surgery for Distant Cutaneous/Subcutaneous or Nodal Metastases 
Patients with Stage IV (i.e. M1a only) melanoma metastatic to skin, subcutaneous sites, or 
distant lymph nodes are allowed. All sites are to be resected with histologically negative 
margins. 

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10.9. 
Appendix 9: Abbreviations 
 
Abbreviation/Term 
Definition 
µg 
Microgram 
µL 
Microliter 
µs 
Microsecond 
Abs 
Absolute 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AJCC 
American Joint Committee on Cancer 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
APM 
Antigen Presenting and Processing Machinery 
aPTT 
Activated Partial Thromboplastin Time 
ASaT 
All Subjects as Treated 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
C1D1 
Cycle 1, Day 1 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
cm 
Centimeter 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CRF 
Case Report Form 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events (version 5.0) 
CTL 
Cytotoxic T Lymphocytes 
DCR 
Disease Control Rate 
PMC 
Protocol Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
DOR 
Duration of Response 
DRE 
Disease Related Events 
ECI 
Events of Clinical Interest 

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Abbreviation/Term 
Definition 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture System 
EOS 
End of Study 
EP 
Electroporation 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HRT 
Hormonal Replacement Therapy 
IB 
Investigator’s Brochure 
iBOR 
Immune Best Overall Response 
iBORR 
Immune Best Overall Response Rate 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
iCPD 
Immune Confirmed Progressive Disease 
iCR 
Immune Complete Response 
IEC 
Independent Ethics Committees 
IFN 
Interferon 
IHC 
Immunohistochemical Method 
IL-12 
Interleukin-12 
IL-2 
Interleukin-2 
IND 
Investigational New Drug application 
INMC 
International Neoadjuvant Melanoma Consortium 
INR 
International Normalized Ratio 
iPFS 
Immune Progression Free Survival 
iPR 
Immune Partial Response 
irAE 
Immune-related Adverse Event 
IRB 
Institutional Review Board 
iRECIST 
Immune Response Evaluation Criteria in Solid Tumor 
iSD 
Immune Stable Disease 

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Abbreviation/Term 
Definition 
iUPD 
Immune Unconfirmed Progressive Disease 
IV 
Intravenous 
LD 
Longest Diameter 
LDH 
Lactate dehydrogenase 
MAF 
Master File 
MDSCs 
Myeloid-Derived Suppressor Cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
mm 
Millimeter 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
NK 
Natural Killer (NK cells) 
NL 
New Lesions 
OMS 
OncoSec Medical Electroporation Therapy System 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cell 
pCR 
Complete pathological response 
PD 
Progression of Disease 
PD-1 
Programmed Cell Death Protein 1 
pDNA 
plasmid DNA 
PET 
Positron Emission Tomography 
pIL-12 
Plasmid Interleukin-12 
PR 
Partial Response 
PT (AE) 
Preferred Term 
PT (lab) 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RFS 
Relapse/Recurrence Free Survival 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 

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Abbreviation/Term 
Definition 
SD 
Stable Disease 
SJS 
Stevens-Johnson syndrome 
SoA 
Schedule of Activities 
SOM 
Sum of Measure 
SUSAR 
Serious Unexpected Suspected Adverse Reaction 
tavo 
Tavokinogene telseplasmid expressing Interleukin-12 
tavo-EP 
Tavokinogene telseplasmid with electroporation 
TEAE 
Treatment Emergent Adverse Event 
TEN 
Toxic Epidermal Necrolysis 
TIL 
Tumor Infiltrating Lymphocytes 
TRAE 
Treatment-related Adverse Events 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
US 
United States 
WBC 
White Blood Cell 
WOCBP 
Woman of Childbearing Potential 

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11. 
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