Conditions: SARS-CoV-2
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 16
Healthy volunteers: yes

Brief summary:
This is a Phase 1, open-label study to evaluate the safety profile of CORVax +/- pIL-12, (electroporated SARS-CoV-2 spike (S) protein plasmid DNA vaccine with or without the combination of electroporated IL-12p70 plasmid.

Detailed description:
This is a Phase 1, open-label study to evaluate the safety profile of CORVax +/- pIL-12, (electroporated SARS-CoV-2 spike (S) protein plasmid DNA vaccine with or without the combination of electroporated IL-12p70 plasmid), given as prime \& boost doses, four weeks apart, in healthy volunteers, divided into age groups of 18-50 versus \> 50 years old. IL-12p70 plasmid DNA electroporation (tavokinogene telseplasmid) has been extensively studied in over 209 subjects across 11 trials including later stage human cancer trials with more than 1000 administrations. The IGEA CLINIPORATOR® system is approved for clinical use in Europe, but remains investigational in this study.

One participant will initially be enrolled to each of four cohorts and monitored over a 7-day DLT window:

1A. Age 18-50; CORVax.

1. B. Age 18-50; CORVax + pIL-12.
2. A. Age \> 50; CORVax.

2B. Age \> 50; CORVax + pIL-12.

If after 7 days, no DLT are observed, the cohort may proceed to enroll a second participant. If after monitoring the second participant for 7 days, no DLT are observed, the cohort may proceed to enroll a third participant. If after monitoring the third participant for 7 days, no DLT are observed, the cohort may proceed to enroll six additional participants, for a total of nine participants per cohort using a (1+1+1, +6) design.

Arms:
arm 1: Healthy volunteers age 18-50 will receive CORVax arm 2: Healthy volunteers age 18-50 will receive CORVax + pIL-12 arm 3: Healthy volunteers age \> 50 will receive CORVax arm 4: Healthy volunteers age \> 50 will receive CORVax + pIL-12

Interventions: intervention 1: CORVax intervention 2: IL-12 plasmid intervention 3: Cliniporator
Intervention descriptions: intervention 1: DNA-encodable coronaviral vaccine intervention 2: cytokine intervention 3: electroporation system

Protocol document:
Prot_SAP_000.pdf: 
 
  
 
 
Page 1 
 
CORVax12 - a phase I trial of SARS-CoV-2 spike (S) protein plasmid DNA vaccine (CORVax) +/- pIL-12 
(tavokinogene telseplasmid) in healthy volunteers, with immunodynamic biomarker monitoring of coordinated 
cellular/humoral response. 
 
 
Version Date:  
 
 
27 January 2021 
 
 
Coordinating Center: 
Providence Portland Medical Center 
Earle A. Chiles Research Institute (EACRI) 
Robert W. Franz Cancer Research Center 
4805 NE Glisan St.  Room 2N35 
Portland, OR  97213 
503-215-6259 
 
Principal Investigator:  
 
Rom Leidner, MD 
 
 
 
 
 
Earle A. Chiles Research Institute (EACRI) 
503-215-5696 
rom.leidner@providence.org 
 
 
Co-Principal Investigator: 
 
Bernard Fox, PhD 
 
Earle A. Chiles Research Institute (EACRI) 
 
 
 
 
 
503-215-6029 
 
 
 
 
 
Bernard.Fox@providence.org 
 
Sub-Investigators: 
 
 
 
Nicholas L. Stucky, MD, PhD 
  Providence Portland Medical Center (PPMC) 
  
Brian Kendall, MD 
  Providence Portland Medical Center (PPMC) 
 
Sasha Stanton, MD, PhD 
  Earle A. Chiles Research Institute (EACRI) 
 
Hong-Ming Hu, PhD 
  Earle A. Chiles Research Institute (EACRI) 
 
William Redmond, PhD 
  Earle A. Chiles Research Institute (EACRI) 
 
Brian Piening, PhD 
  Earle A. Chiles Research Institute (EACRI) 
 
Brady Bernard, PhD 
  Earle A. Chiles Research Institute (EACRI) 
 
Carlo Bifulco, MD 
  Earle A. Chiles Research Institute (EACRI) 
 
Yoshinobu Koguchi, MD, PhD 
  Earle A. Chiles Research Institute (EACRI) 
 
Eric Tran, PhD 
  Earle A. Chiles Research Institute (EACRI) 
 
Walter Urba, MD, PhD 
  Earle A. Chiles Research Institute (EACRI) 
 
Shawn Jensen, PhD 
  Earle A. Chiles Research Institute (EACRI) 
 
Christopher Twitty, PhD  
  OncoSec Medical Incorporated (OncoSec)


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PROTOCOL SIGNATURE PAGE 
 
 
 
Protocol Number:  
 
 
Protocol Title: CORVax12 - a phase I trial of SARS-CoV-2 spike (S) protein plasmid DNA vaccine (CORVax) +/- pIL-12 
(tavokinogene telseplasmid) in healthy volunteers, with immunodynamic biomarker monitoring of coordinated 
cellular/humoral response. 
 
                 
I have read this protocol and agree that it contains all necessary details for carrying out this study.  I will conduct the 
study as outlined herein and will complete the study within the time designated, in accordance with all stipulations of the 
protocol and in accordance with Federal Regulations, Good Clinical Practices, and local regulatory requirements.  
 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who assist regarding 
the study agent(s) and the conduct of the study.  
 
 
 
 
 
 
 
 
 
 
 
 
     
  
     9/29/2020 
Rom Leidner, MD 
 
 
 
 
 
 
 
 
 
 
Investigator Name (print) 
 
 
Investigator Signature  
 
Date 
 
 
 
 
 
 
 
     
  
     9/29/2020 
Bernard Fox, PhD 
 
 
 
 
 
 
 
 
 
 
Investigator Name (print) 
 
 
Investigator Signature  
 
Date 
 
 
 
 
 


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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ........................................................................................................................................ 2 
1. 
RATIONALE ................................................................................................................................................................. 5 
2. 
BACKGROUND ........................................................................................................................................................... 5 
3. 
OBJECTIVES & SCHEMA ........................................................................................................................................... 8 
4. 
PARTICIPANT SELECTION ........................................................................................................................................ 9 
4.1 
Inclusion Criteria ............................................................................................................................................... 9 
4.2 
Exclusion Criteria .............................................................................................................................................. 9 
5. 
REGISTRATION & CANCELLATION GUIDELINES ................................................................................................ 10 
6. 
STUDY DESIGN ......................................................................................................................................................... 10 
6.1 
Sentinel / Safety Run-In .................................................................................................................................. 10 
6.2 
Dose Limiting Toxicity ..................................................................................................................................... 11 
6.3 
Stopping Rules ............................................................................................................................................... 11 
6.4 
Dose Delays ................................................................................................................................................... 12 
6.5 
Subject Discontinuation & Replacement ........................................................................................................ 12 
7. 
STUDY CALENDAR .................................................................................................................................................. 13 
8. 
ADMINISTRATION OF STUDY TREATMENTS ....................................................................................................... 14 
8.1 
Accountability and Compliance of Investigational Product ............................................................................. 14 
8.2 
CORVax (SARS-CoV-2 (S) protein plasmid DNA vaccine) ............................................................................ 14 
8.2.1 Cohorts 1A & 2A - Intradermal CORVax only ................................................................................................ 15 
8.3 
pIL-12 (tavokinogene telseplasmid) ................................................................................................................ 15 
8.3.1 Cohorts 1B & 2B - Intradermal CORVax + pIL-12 .......................................................................................... 16 
8.4 
Electroporation: IGEA CLINIPORATOR® with IGEA Applicator ..................................................................... 16 
8.4.1 All Cohorts - Intradermal EP ........................................................................................................................... 17 
8.5 
Plasmid Injection followed by Electroporation (EP) ........................................................................................ 17 
8.5.1 Clinical Administration Technique .................................................................................................................. 18 
8.5.2 Monitoring Plan on Day of Administration ...................................................................................................... 19 
8.5.3 Cohorts 1A & 2A: CORVax ............................................................................................................................. 19 
8.5.4 Cohorts 1B & 2B: CORVax + pIL-12 .............................................................................................................. 19 
8.6 
Durable Procedural Pain Assessment ............................................................................................................ 19 
8.7 
Management of Clinical Toxicity ..................................................................................................................... 19 
8.8 
Reporting Product Complaints ........................................................................................................................ 20 
9. 
IMMUNODYNAMIC BIOMARKERS .......................................................................................................................... 20 
9.1 
Immunologic Monitoring ................................................................................................................................. 20 
9.2 
Neutralization assay ....................................................................................................................................... 20 
9.3 
Cytokines ........................................................................................................................................................ 20 
9.4 
T cell response ............................................................................................................................................... 21 
9.5 
B cell response ............................................................................................................................................... 21 
9.6 
Coordinated humoral/cellular response .......................................................................................................... 21 
9.7 
Whole genome sequencing ............................................................................................................................ 21 
9.8 
Clinical Outcomes and Surveillance Database .............................................................................................. 21 
10. REGULATORY & REPORTING REQUIREMENTS .................................................................................................. 21 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) ........................................................................ 21 
10.2 
Definitions ....................................................................................................................................................... 21 
10.3 
Adverse Event Reporting ................................................................................................................................ 22 
10.4 
Continuing Review and Final Reports ............................................................................................................ 23 
10.5 
Protocol Modifications and Amendments ....................................................................................................... 23 
10.6 
Record Retention ............................................................................................................................................ 23 
10.7 
Oversight and Monitoring Plan ....................................................................................................................... 24 
10.8 
Quality Assurance ........................................................................................................................................... 24 
10.9 
Case Report Forms (CRFs) ............................................................................................................................ 24 
11. STATISTICAL CONSIDERATIONS........................................................................................................................... 24 


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11.1 
Sample Size and Statistical Analysis .............................................................................................................. 24 
11.2 
Participant Accrual .......................................................................................................................................... 25 
APPENDIX 1: Toxicity Grading Scale ............................................................................................................................. 26 
APPENDIX 2: Medically Attended Adverse Events - pIMMCs ...................................................................................... 30 
REFERENCES ................................................................................................................................................................... 32 
 


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1. RATIONALE 
DNA vaccines have been widely explored and remain a promising immunotherapeutic strategy suitable for infectious 
diseases. DNA vaccines could represent an affordable, safe and effective alternative to conventional vaccines. 
Plasmid DNA-based vaccines are considerably faster and easier to manufacture than most other vaccine platforms. 
Further, DNA-encodable prophylactic vaccines with electroporation represent a safe and effective approach to initiate 
both humoral and cellular immunity in healthy volunteers directed at a variety of infectious diseases, including 
coronavirus.  
 
The choice of immunogen for a DNA-encodable coronaviral vaccine is critical for not only the magnitude but also 
quality of immune response. The coronavirus spike (S) protein is composed of two subunits; the S1 subunit contains 
a receptor-binding domain that engages with the host cell receptor angiotensin-converting enzyme 2 (ACE2) and the 
S2 subunit allows viral-cell membrane fusion. Collectively, the S protein has been shown to induce long-term and 
potent neutralizing antibodies and/or protective immunity in various preclinical severe acute respiratory syndrome 
(SARS)-CoV studies and in both preclinical and clinical studies in Middle East Respiratory Syndrome (MERS)-CoV 
studies. These previous vaccine studies, which were based on the spike protein from different strains of coronavirus, 
provide an immunological framework for this vaccine concept.  
 
While the immunological data from these related (S) protein vaccines are foundational for our SARS-CoV-2 (severe 
acute respiratory syndrome coronavirus 2) vaccine, there remains a possibility that targeting a frequently mutated viral 
sequence with the potential for antigenic drift may limit the efficacy of this approach. However, genetic alignments of 
multiple reported SARS-CoV-2 strains point to a relatively conserved sequence even among the recently described 3 
clades1,2. The S protein construct used in this proposal originated in Dr. Barney Graham’s Viral Pathogenesis 
Laboratory at the NIH (National Institute of Allergy and Infectious Diseases) and represents a highly conserved 
consensus sequence based on the first reported SARS-CoV-2 sequences. Further, our group evaluated approximately 
one hundred DNA sequences of SARS-CoV-2 cases in the USA that were downloaded from GISAID (Global Initiative 
on Sharing All Influenza Data, gisaid.org – accessed March 16, 2020). All sequences of the ‘S’ gene, coding for spike 
(S) glycoprotein, were aligned to reference gene ID 43740568 (NC_045512.2 bases 21563-25384). Multi-sequence 
alignment of these ~100 gene sequences resulted in no alignment gaps (i.e., no indels or significant structural 
alterations). The aligned DNA sequences were translated to amino acids and evaluated for percent identity to the 
reference protein sequence. All positions of spike (S) glycoprotein had 100% identity to reference with the exception 
of amino acids H49 (99%), F157 (99%), G181 (99%), V483 (96%), D614 (97%), and H655 (99%). Notably, V483 is in 
the receptor-binding domain (RBD) to angiotensin-converting enzyme 2 (ACE2); however, this position is not a contact 
residue, it is merely an alanine substitution, and is of low conservation among homologous coronavirus strains. 
 
Interleukin 12 (IL-12) plays an integral role in the induction of a Th1-biased response while coordinating both the 
innate and adaptive immune systems.  Besides triggering cellular immunity, IL-12 can also augment antigenicity via 
activation of antigen presenting cells as well as assist the humoral response by encouraging isotype switching towards 
a more functional antibody. With the inclusion of IL-12, the proposed vaccination (CORVax12) is designed to drive a 
coordinated immune response, capable of drawing upon the innate, adaptive humoral, and adaptive cellular arms. 
This multi-pronged immunity is likely to be important at generating robust anti-viral responses as previous studies with 
SARS-CoV identified a critical role for each component. 
 
Based on these data we consider that vaccination with the proposed SARS-CoV-2 (S) protein plasmid provides an 
opportunity to evaluate whether vaccination alone or combined with IL-12 is safe, provides a strong neutralizing Ab 
response to the virus, and induces a T cell response to viral antigens.  
 
 
2. BACKGROUND 
Coronaviruses, which can infect and cause disease in both mammals and birds, typically lead to mild respiratory 
infections such as the common cold. However, although rare, coronavirus strains such as Severe Acute Respiratory 
Syndrome (SARS-CoV) and Middle East Respiratory Syndrome (MERS-CoV) can be lethal.  
 
On December 31, 2019, a novel strain of coronavirus, coined SARS-CoV-2 by the World Health Organization (illness 
from SARS-CoV-2 is COVID-19), was discovered after tracing the origins of a pneumonia outbreak in Wuhan, China. 
SARS-CoV-2 identifies as a novel strain of betacoronavirus that is capable of person-to-person spread3. Previous 
international emergency betacoronavirus outbreaks include both the genetically similar SARS-CoV (Severe Acute 
Respiratory Syndrome) and MERS-CoV (Middle East Respiratory Syndrome)4. 


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The World Health Organization has determined the COVID-19 outbreak to be a global pandemic.  To combat the rapid 
spread of the virus, governments across the world, including the United States, have taken steps to limit spread, 
including travel restrictions, sheltering in place, and quarantines. Because coronaviruses typically present with 
symptoms mirroring the common cold, there has historically been a low interest in developing an antiviral. However, 
with the progression of the current pandemic, the need to develop vaccines that can help contain these viruses has 
become clear. 
 
As further described below, Drs. Leidner, Fox, and colleagues have worked with researchers at OncoSec Medical 
Incorporated (OncoSec) to develop a novel vaccine approach for COVID-19. The plan is to employ OncoSec’s 
proprietary gene delivery system, using established electroporation technology to deliver a plasmid-based DNA 
vaccine encoding the SARS-CoV-2 spike (S) glycoprotein together with a plasmid encoding IL-12p70.  
 
Here, we describe both a novel DNA-encodable vaccine approach which includes the use of the IGEA 
CLINIPORATOR® - Model EPS02 ("CLINIPORATOR") generator, which provides a favorable transfection profile. The  
CLINIPORATOR® generator achieves its high transfection efficiency by using a lower voltage with longer duration 
pulses, which, based on preclinical evaluation of OncoSec's generator (with identical electroporation parameters), 
have resulted in improved expression of the electroporated genes.  
 
Vaccination with Electroporation (EP): Its Mechanism and Advantages  
 
DNA vaccines can be delivered with viral and bacterial vectors but are 
often limited by poor transfection rates and/or rapid clearance by 
neutralizing antibodies 5,6. Alternative methods of delivering DNA vaccines, 
such as electroporation, continue to be explored. Electroporation (EP) is a 
technique that applies electric pulses to transiently permeabilize a cell 
membrane, thereby promoting uptake of macromolecules such as nucleic 
acids into the cell. In vivo EP has been used in many clinical trials to deliver 
DNA vaccines and drugs to various tissues7. Importantly, it has been 
shown to dramatically improve gene delivery (100-1000-fold), which is 
foundational to the immunogenicity of DNA vaccines8,9.   
 
The location and cellular architecture of the tissue into which DNA vaccines 
are delivered can modulate the effectiveness and/or type of immune 
response that is generated. EP-mediated delivery targeting the skin has 
been attracting considerable attention10. Skin is the most accessible organ 
and, in part due to an abundance of antigen presenting cells (APC) such 
as Langerhans cells and skin-resident dendritic cells, is highly efficient at 
presenting antigens and priming an effective cellular (T cell-mediated) anti-
viral response10,11. With the use of the  CLINIPORATOR® electroporation 
device, we will target the skin, as it has been successfully transfected using 
low-voltage parameters with a DNA-based reporter protein (Fig.1) and has 
lower levels of pain and toxicity 
 
This clinical trial will evaluate the safety and anti-viral immune stimulating 
efficacy of combining electroporation of plasmid encoding both the 
coronavirus spike (S) glycoprotein and IL-12. IL-12 is a proinflammatory 
cytokine known to efficiently support NK and macrophage function as well as to polarize a Th1-biased T cell response. 
Previous viral studies have demonstrated an increase in both cellular and humoral immune responses upon delivery 
of DNA-encodable IL-12 via electroporation12. Additionally, control of the SIV/HIV infection correlated strongly with the 
IL-12-mediated increase of SIV-specific CD8+ and CD4+ T cells13. Together, a strong rationale is evident for 
combination immunotherapy including plasmids encoding both the SARS-CoV-2 (S) protein and IL-12 (together, 
CORVax12). The IL-12 plasmid employed in this study has been used as intratumoral treatment in eight clinical trials 
with evidence of increased immune infiltrates and anticancer effects.  
 
Combination of IL-12 with a Vaccine Directed Against SARS-CoV-2 Spike (S) Glycoprotein  
  
Currently, little is known about the mechanisms of transmission, infection, and immunity related to SARS-CoV-2. 
However, phylogenetic analyses have revealed that of all the viral strains from the family Coronaviridae, SARS-CoV-
 
 
Figure 1. Expression of luciferase 48 
hrs following intradermal injection and 
electroporation of luciferase plasmid. 


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2 shares the greatest similarity with the severe acute respiratory syndrome (SARS) strain1,14. In fact, three strains of 
SARS-CoV-2 together with two bat-derived SARS-like strains, form a distinct clade of coronaviruses 3.  
 
The antigenic foundation of this prophylactic vaccine, SARS-CoV-2’s spike 
(S) glycoprotein, was selected based on demonstrated immunogenicity (both 
cellular and humoral), as well as previously having been identified as an 
appropriate antigen to drive anti-viral responses in other strains of 
coronavirus including 15–17SARS and MERS. Further, multiple isolates of 
SARS-CoV-2 have identified a relatively conserved genetic sequence that 
codes for the (S) protein with limited synonymous mutations between 
strains14,18, which may help to limit immune escape variants seen with other 
unstable genetic elements. To this point, OncoSec has secured and will use 
the augmented DNA-encodable spike protein developed in Dr. Barney 
Graham’s laboratory at the NIH1 as the antigenic component of the vaccine. 
 
OncoSec is a cancer immunotherapy company with extensive experience in 
delivering therapeutic levels of DNA-encoded IL-12 (interleukin-12 plasmid, 
tavokinogene telseplasmid) via reversible electroporation. OncoSec has 
demonstrated that intratumoral electroporation of plasmid IL-12 can prime 
significant frequencies of proliferating antigen-specific CD8+ T cells in the 
spleen of treated mice19 as well as memory subsets in on-treatment 
responding patients 20 (Fig 2). These and other clinical studies, along with an 
abundance of historic IL-12 data, support the inclusion of this cytokine in the 
CORVax12 vaccine platform.  
 
The design of this clinical trial will evaluate whether the addition of IL-12 to 
the vaccination strategy will augment the adaptive anti-SARS-CoV-2 immune 
response. While protection against SARS-CoV-2 infection appears to be 
mediated by neutralizing Ab, cellular immunity has been shown to play a large 
role in controlling SARS-CoV, with both innate (NK) and adaptive (CD4+ T 
cells) arms providing critical Th1-directed cytokines such IFN-γ and TNF-
α21,22. These data underscore the rationale for testing the addition of IL-12, a 
cytokine that can augment priming of Type 1 T cell responses and augment 
effector function of T cells and NK cells23.   
 
Antibody-dependent enhancement (ADE) concerns 
 
The phenomenon of antibody-dependent enhancement (ADE) has been 
reported for dengue24,  HIV-125,  and influenza26. Wang et al, demonstrated 
experimentally that monoclonal antibodies to SARS-CoV spike protein 
resulted in ADE, as did highly diluted anti-sera27, whereas polyclonal, 
undiluted anti-sera, neutralized SARS-CoV infection. Inclusion of IL-12 in the vaccine platform under study may further 
safeguard against ADE, acting as the adjuvant to trigger both the effector CD8+ T cell response as well as the 
complimentary CD4+ T cell response which can deepen the humoral response. 
 
Rationale for vaccine route of administration and dose 
 
The rationale for administering plasmid encoding the SARS-CoV-2 (S) protein to the dermis includes several points. 
We hypothesize that dermal expression of both IL-12 and SARS-CoV-2 (S) protein will result in limited expression 
within the nearby dermis, leading to antigen presentation in the draining lymph node that, secondary to the influence 
of IL-12, will result in the priming of an anti-viral immune response that is polarized to a type 1 immunity. By comparing 
the immune response of subjects receiving SARS-CoV-2 (S) alone with those receiving SARS-CoV-2 (S) plus IL-12, 
we will be able to test our hypothesis that inclusion of IL-12 will augment the magnitude and breadth of the T and B 
cell anti-viral response. The rationale for the dose of 0.8 mg into the dermis is based on the relatively small differences 
in the antibody response of subjects receiving electroporation of plasmid vaccines12. Further, a current vaccine study 
for SARS-CoV-2 is electroporating 1 or 2 mg of plasmid into the dermis. In this study subjects will receive either 0.8 
mg of spike protein alone or 0.8 mg of spike protein combined with 0.8 mg of IL-12 plasmid. 
 
 
A 
 
B 
 
 
 
Figure 2: (a) electroporation of 
plasmid IL-12 generates 
proliferating, antigen-specific 
splenocytes by day 7 (b) Increased 
frequency of proliferating memory 
CD8+T cells in the periphery is 
significantly increased in 
responders on treatment 


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Rationale for parallel age cohorts 
 
The mortality and morbidity burden of COVID-19 is overwhelmingly among individuals over the age of 50, yet the 
convention in early phase vaccine trials has been to test in the 18 to 50 year age bracket. Therefore, we have designed 
this phase 1 trial to assess the safety profile of this vaccine platform in two age groups: 18 to 50 years, as is convention; 
but also, and we think importantly, in parallel cohorts from the over 50 age bracket, a decision which is warranted by 
the extraordinary circumstances of the current pandemic. It will be essential to know that this vaccine is safe in the 
over 50, at-risk population. Not to do so, could delay safety ascertainment for the target population and hinder 
detection of early efficacy signals that might otherwise surface for the at-risk demographic, in the event of rebound or 
seasonal cycling of SARS-CoV-2. 
 
 
3. OBJECTIVES & SCHEMA 
Primary Objective 
To determine the safety profile of CORVax +/- pIL-12 in healthy volunteers, age 18-50 or age > 50. 
 
Outcome Measures 
• 
Toxicity and Adverse Events (AEs) based on FDA Guidance for Industry 2005D-0155: Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
• 
90 day monitoring of hematology, serum chemistry, and creatine phosphokinase. 
• 
90 day monitoring of serial physical exam, vital signs, and durable pain score. 
• 
Extended monitoring of Medically Attended Adverse Events (MAAEs) for potentially immune-mediated 
conditions (pIMMCs) 
 
Exploratory Objectives 
Immunodynamic biomarkers (section 9). 
 
Outcome Measures 
• 
Blood sampling for plasmid expression levels and immune response measurements will occur on days 1, 2, 
3, 15, 30, 31, 32, 45, 60 and 90 of study.  
• 
The main objectives of the monitoring will be to characterize both the humoral and cellular immune response 
to the pUMVC3-CORVax vaccine. 
  
 
 
Day
1,2,3
CORVax
Day 1
15
30,1,2
45
...…  18 months
Cohort 1A
n = 9
(1+1+1, +6)
60
90
Ages 18 - 50
CORVax
Day 30
CORVax
Day 1
Cohort 1B
n = 9
(1+1+1, +6)
CORVax
Day 30
pIL-12
Day 30
pIL-12
Day 1
CORVax
Day 1
Cohort 1A
n = 9
(1+1+1, +6)
CORVax
Day 30
CORVax
Day 1
Cohort 1B
n = 9
(1+1+1, +6)
CORVax
Day 30
pIL-12
Day 30
pIL-12
Day 1
Blood
1,2,3
15
30,1,2
45
...…  18 months
60
90
Day
Blood
Ages > 50
CORVax: (S) protein
Intradermal 0.8 mg (500 uL)
plasmid DNA electroporation
IL-12 plasmid
Intradermal 0.8 mg (250 uL)
plasmid DNA electroporation
Healthy volunteers, n = 36
-
CORVax +/- pIL-12 
-
Age 18-50  vs.  > 50
monitor 18 months for pIMMCs


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4. PARTICIPANT SELECTION 
4.1 Inclusion Criteria 
 
4.1.1 
Healthy adult volunteers ages 18 years and above, who are able to provide written informed consent 
and willing to allow storage and future use of samples for SARS-CoV-2 related research.   
4.1.2 
Women of childbearing potential (WOCBP) must have negative serum or urine pregnancy on each 
day of vaccine administration. 
4.1.3 
Males and women of childbearing potential must agree to take appropriate precautions to avoid 
pregnancy during treatment and through 180 days after last dose of IP. 
 
4.2 
Exclusion Criteria 
4.2.1 
Current or previous SARS-CoV-2 infection or receipt of an experimental treatment for prevention of 
SARS-CoV-2. 
4.2.2 
Administration of any vaccine within 4 weeks of first dose. 
4.2.3 
Any laboratory abnormalities at baseline greater than Grade 1 per the ”FDA Guidance for Industry: 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials”: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/toxicity-
grading-scale-healthy-adult-and-adolescent-volunteers-enrolled-preventive-vaccine-clinical 
4.2.4 
Any history of cardiac arrhythmia. 
4.2.5 
Any history of epilepsy or seizure within the last five years.  
4.2.6 
Use of immunosuppressive medication within 14 days before the first dose of study drug.  
4.2.7 
Anticipated treatment with TNF-α inhibitors (e.g., infliximab, adalimumab, or etanercept). 
4.2.8 
Pregnancy or breastfeeding. 
4.2.9 
Body mass index of 35 kg/m2 or more. 
4.2.10 
Administration of any monoclonal or polyclonal antibody product within 4 weeks of the first dose. 
4.2.11 
Chronic liver disease or cirrhosis. 
4.2.12 
Previous major surgery or any radiation therapy within 4 weeks of group assignment. 
4.2.13 
Any pre-excitation syndromes (e.g., Wolff- Parkinson-White syndrome). 
4.2.14 
Metal implants within 20cm of the planned site(s) of injection; presence of keloid scar formation or 
hypertrophic scar as a clinically significant medical condition at the planned site(s) of injection; tattoos 
covering the injection site area. 
4.2.15 
Presence of a cardiac pacemaker or automatic implantable cardioverter defibrillator. 
4.2.16 
History of allogeneic organ transplantation. 
4.2.17 
History of primary immunodeficiency.  


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4.2.18 
Known HIV, hepatitis B virus, or hepatitis C virus infection. Participants with a past or resolved HBV 
infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are 
eligible. 
4.2.19 
Uncontrolled intercurrent illness, including but not limited to symptomatic congestive heart failure, 
uncontrolled hypertension, unstable angina pectoris, unstable cardiac arrhythmia, interstitial lung 
disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric 
illness/social situations that would limit compliance with study requirement, substantially increase risk 
of incurring AEs or compromise the ability of the participant to give written informed consent.  
4.2.20 
Comorbidities, controlled or otherwise, associated with higher risk for severe COVID-19 illness - 
because our understanding of the pathogenesis of SARS-CoV-2 continues to evolve, this will be 
based on most current information available at time of screening regarding risk factors for severe 
disease, using resources such as those described on the Centers for Disease Control website: 
https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-at-higher-risk.html 
4.2.21 
Subjects at high-risk for SARS-CoV-2 exposure per investigator, including healthcare workers, first 
responders, and individuals with known exposure to individuals infected with SARS-CoV-2. 
4.2.22 
Active infection including tuberculosis (clinical evaluation that includes clinical history, physical 
examination and radiographic findings, and TB testing in line with local practice).  
4.2.23 
History of autoimmune or inflammatory disorders including but not limited to inflammatory bowel 
disease (e.g., colitis or Crohn's disease), diverticulitis (with the exception of diverticulosis), systemic 
lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with 
polyangiitis), Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, (see Appendix 2).  
4.2.24 
Known allergy or hypersensitivity to study drug(s) or compounds of similar biologic composition to the 
study drug(s), or any of the study drug excipients.  
4.2.25 
Investigator discretion relating to any condition which might interfere with study requirements.  
 
5. REGISTRATION & CANCELLATION GUIDELINES 
Subjects must meet all of the eligibility requirements and undergo all pre-study procedures. Subjects will be 
randomized 1:1 for enrollment to cohort A or B, within their age group (age 18-50 or > 50).  Study Numbers will be 
assigned at enrollment based on the EACRI Immune Monitoring Laboratory (IML) sample ID nomenclature per order 
of enrollment. All reports & research specimens, including immune parameters or PK/PD, will be labeled with full 
subject Study Number.   
 
If a subject enrolls in the study, but does not receive study therapy, the subject's enrollment may be canceled.  
Reasons for cancellation will be documented in writing.  Subjects whose enrollment was canceled before receiving 
study therapy will be replaced.  
 
 
 
6. STUDY DESIGN 
6.1 
Sentinel / Safety Run-In 
This is a Phase 1, open-label study to evaluate the safety profile of CORVax +/- pIL-12, (electroporated SARS-CoV-
2 spike (S) protein plasmid DNA vaccine with or without the combination of electroporated IL-12p70 plasmid), given 
as prime & boost doses, four weeks apart, in healthy volunteers, divided into age groups of 18-50 versus > 50 years 
old. IL-12p70 plasmid DNA electroporation (tavokinogene telseplasmid) has been extensively studied in over 209 
subjects across 11 trials including later stage human cancer trials with more than 1000 administrations. The IGEA  
CLINIPORATOR® system is approved for clinical use in Europe, but remains investigational in this study.  


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The known side effects seen after the use of the electrode and the application of the electroporation treatment, 
included injection site pain, redness, swelling, rash, erythema and slight edema, skin exfoliation may be 
present in the treatment area. These signs usually disappear completely within a few days. The subject may 
develop superficial abrasions of the epidermis caused by the electrode. The subject's skin may form a crust on 
the treated area, followed by scarring. Redness or scaling were observed four weeks after the treatment in 
some subjects.  
Pain and muscle contraction with EGT mode is limited. Superficial local anesthesia with lidocaine could be 
considered in order to reduce the discomfort during needles penetrations. 
There are no other side effects which have been reported  with the use of the device. 
 
The device uses the same low voltage parameters that have been used in a pre-clinical setting and has been shown 
to safely transfect plasmids via intradermal routes of delivery. The SARS-CoV-2 spike (S) protein plasmid DNA vaccine 
is a novel agent. Because this represents a first-in-human combinatorial approach, an initial 1+1+1 sequential safety 
run-in will be conducted to cautiously assess for dose limiting toxicity (DLT).  
 
One participant will initially be enrolled to each of four cohorts and monitored over a 7-day DLT window:  
 
1A.  Age 18-50; CORVax. 
1B.  Age 18-50; CORVax + pIL-12. 
2A.  Age > 50; CORVax. 
2B.  Age > 50; CORVax + pIL-12.  
 
If after 7 days, no DLT are observed, the cohort may proceed to enroll a second participant.  If after monitoring the 
second participant for 7 days, no DLT are observed, the cohort may proceed to enroll a third participant. If after 
monitoring the third participant for 7 days, no DLT are observed, the cohort may proceed to enroll six additional 
participants, for a total of nine participants per cohort using a (1+1+1, +6) design.  
 
6.2 
Dose Limiting Toxicity 
Toxicity and AE assessment is adapted from the 2005D-0155 FDA Guidance for Industry: Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (see Appendix 1).  Relational 
attribution of AEs will be determined by the investigator as: definitely/probably/possibly/not related to study treatment; 
immune-related yes/no; autoimmune definitely/probably/possibly/not; and expected/unexpected.   
 
Any AEs considered as definitely/probably autoimmune, and lasting more than 7 days, will be categorized as 
unexpected and as a pIMMC (see Appendix 2). 
 
Dose limiting toxicity (DLT) is defined as any Serious Adverse Event (SAE) or a Grade 3 or higher toxicity that in the 
opinion of the investigator is considered at least possibly related to study treatment. 
  
6.3 
Stopping Rules 
The safety stopping rules will be applied to terminate a specific study cohort if more than one of the first three 
participants in the cohort suffers DLT which includes any SAE considered at least possibly related during the initial 7-
day sequential DLT run-in (1+1+1); or at any time thereafter, if more than two participants in the cohort experience 
DLT (1+1+1, +6).  
 
For the day-30 “boost” vaccination, the same 7-day sequential DLT run-in design (1+1+1, +6), and the same safety 
stopping rules apply. 
 
Study enrollment and dosing will be halted if the following safety events are observed with the vaccination or the 
electroporation (EP) administration:  
• 
20% or more of subjects across all cohorts (7 or more subjects) experience the same or similar Grade 3 or 
higher adverse events assessed as at least possibly related to study treatment. 
• 
Any death or SAE assessed as at least possibly related to study treatment. 
• 
Any newly diagnosed pIMMC assessed as at least possibly related to study treatment. 
• 
Any incidental or incorrect voltage or pulse delivery outside the specifications outlined in the User Manual 


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In the event study halting rules are triggered, the study’s safety committee will review all available safety information, 
and determine whether enrollment and dosing are reasonably safe to continue for either or both vaccine formulations.  
The safety committee is comprised of three physicians with expertise in immunology who are not investigators on the 
study: Dr. Brendan Curti, Dr. Matthew Taylor, and Dr. David Page.  The committee’s review and determination will be 
documented and submitted to the IRB and FDA. 
 
6.4 
Dose Delays 
Treatment delay will be allowed for subjects with fever or other signs of an active infection on the day of planned 
vaccine administration, to include any evidence of infection upon evaluation of the administration sites. Treatment 
delay should continue until > 48 hours resolution of fever or other signs of active infection. In the event a subject 
reports symptoms consistent with COVID-19 or known exposure in the interval between 1st and 2nd vaccination, 
treatment delay is indicated until repeat COVID-19 qPCR is confirmed as negative, before proceeding with study 
treatment. 
 
6.5 
Subject Discontinuation & Replacement 
In the event of a positive COVID-19 qPCR test result during the interval between 1st and 2nd vaccination, subject will 
discontinue study treatment and may be replaced. In the event of treatment delay exceeding 21 days, and absent 
DLT, subject will discontinue study treatment and may be replaced. In the event of a confirmed positive serum or urine 
pregnancy test, between 1st and 2nd vaccination, subject will discontinue study treatment and may be replaced. And 
otherwise, subjects who enroll in the study, and do not complete study treatment for reasons other than DLT, may be 
replaced.  
 
Discontinuation for the following reasons does not allow for subject replacement: an SAE assessed as 
definitely/probably related to the investigational product; any Grade 3 or higher unsolicited AE, assessed as 
definitely/probably related to the investigational product; a new medical condition that would qualify for study exclusion; 
suspicion or diagnosis of pIMMC, as per section 6.1. 
 
 
 
 


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7. STUDY CALENDAR 
Schedule of Events 
Screen 
Day -9 to 1 
Day 
1 
Day 
2,3 
Day 
15 
Day 
30 
Day 
31,32 
Day 
45 
Day 
60 
Day 
90 
Window (days) 
 
 
 
+/-1 
+/-1 
+/-1 
+/-1 
+/-2 
+/-2 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical history, EKG1 
X 
 
 
 
 
 
 
 
 
Microbiome specimens2 
X 
 
 
 
 
 
 
 
 
NGS whole genome2 
X 
 
 
 
 
 
 
 
 
HIV, HBV, HCV serology2 
X 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
X 
 
 
 
X 
COVID-19 qPCR & serology2,3,8 
X 
 
 
 
X3,8 
 
 
X 
X8 
CMP, CPK, CBC w/ diff 
X 
X 
X 
X 
X 
X 
X 
X 
X 
UA and sediment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immune parameters2 
 
X 
X 
X 
X 
X 
X 
X 
X 
b-HCG4 
 
X 
 
 
X 
 
 
 
 
Vital signs5 
 
X 
 
X 
X 
 
X 
 
 
CORVax6 
(intradermal) 
 
X 
 
 
X 
 
 
 
 
pIL-126 
(intradermal) 
 
Cohorts 
1B, 2B 
 
 
Cohorts 
1B, 2B 
 
 
 
 
Adverse events7 
 
X 
 
X 
MAAEs8 
 
X 
MAAEs8 
MAAEs8 
Concomitant medications9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
1. Electrocardiograms (EKG) to include: heart rate (beats/min), PR interval (ms), QRS interval (ms), RR interval (ms), QT interval 
(ms), QTcB interval (ms), QTcF interval (ms), sinus rhythm (yes/no), and overall evaluation (normal/abnormal). 
2. Refer to Lab Manual; microbiome specimens may be collected at any time up until start of study treatment. Refer to Lab 
Manual; 50mL whole blood in heparinized tubes (green top) and 5mL serum in SST tube; always collect pre-treatment on 
relevant study days; collect double baseline set on Day 1 of study. 
3. COVID-19 testing should be repeated at any time prior to 2nd vaccination if report of symptoms consistent with COVID-19 or 
known exposure. This will be performed using the Roche cobas® SARS-CoV-2 qPCR nasal swab and DiaSorin LIAISON® 
SARS-CoV-2 S1/S2 IgG serology platforms, (or updated institutional standard, at time of testing). 
4. Serum or urine b-HCG (for WOCBP only) confirmed negative result on the day of vaccine administration.   
5. Height at initial visit only; other vital signs at every indicated time point. 
6. Refer to Procedure Manual for detailed administration instructions; monitor participants 1 hour post-treatment with vital signs 
q30 minutes x2, starting 10-15 minutes post vaccination; vitals review by study investigator required prior to release from clinic. 
7. Adverse events/toxicity daily query by use of diary or RN/CRC phone call for seven days following each vaccination, including 
but not limited to injection site pain, redness, swelling, fatigue, headache, nausea, vomiting, diarrhea, myalgia, arthralgia, rash, 
new pain, dyspnea and temperature (see Appendix 1: Toxicity Grading).  Subjects utilizing the diary for AE collection will be 
called on Day 7 by RN/CRC to review diary entries.  On days 1, 15, 30, 45 where vital signs are indicated, AE assessment 
should be conducted in person by RN, or other PI designee. 
8. Monitor for MAAEs at months 1, 2, 3, 6, 12 and 18 with contact by research RN or research associate for potentially immune-
mediated medical conditions (see Appendix 2: MAAEs/pIMMCs); repeat COVID-19 qPCR and antibody testing to be performed 
at any time during the 18 months safety monitoring in the event of potential exposure to SARS-CoV-2 (i.e., close contact tests 
positive for SARSCoV-2) or symptoms of SARS-CoV-2 infection, with full immunodynamic profiling (section 9) to be performed 
at the same time. In addition, voluntary extended immune monitoring under longitudinal research specimen protocol, will be 
offered to all study subjects at day 90.  
9. Concomitant medications (including those administered prophylactically) will be collected from 30 days prior to Day 1 through 
Day 90.  In addition, all medications associated with SAEs, MAAEs (including pIMMCs) will be collected through 18 months.  
 
 


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8. ADMINISTRATION OF STUDY TREATMENTS 
8.1 Accountability and Compliance of Investigational Product 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. The 
Investigational Pharmacist will manage drug accountability records. The Investigator or pharmacist/designee may 
dispense study medication(s) and device components for only subjects enrolled in the study. Individual subject 
accountability records must be kept by the site staff. The subject number, the date, batch number/wallet number, and 
quantity of study medication used or returned by the subject, as well as device and device components will be recorded 
on the appropriate accountability forms by the site staff. These records and the inventory of study medication, device 
and device components on site will be verified by the study monitor for accuracy and completeness on an ongoing 
basis throughout the study. Unused drug supplies will be disposed of as instructed in the Study Pharmacy Manual. 
 
Treatment compliance will be assessed at all visits during the study. It will be based on accountability records and an 
inventory of used/unused supplies. All Investigational Drug Product should be retained at the study site appropriately. 
At the end of the study, the monitor will conduct a final drug reconciliation for all subjects and the study site overall. 
All records of study medication administration, accountability records and drug disposition records will be examined 
and reconciled by the study monitor. Only upon the site monitor completing final drug reconciliation at the site will your 
monitor authorize the destruction of the unused Investigational Drug Product as directed by UbiVac, OncoSec and the 
institutional requirements.  
 
 
8.2 CORVax (SARS-CoV-2 (S) protein plasmid DNA vaccine)   
How Supplied 
CORVax is formulated in phosphate buffered saline (PBS) for intradermal injection followed by in 
vivo electroporation. GLP-grade CORVax is manufactured by UbiVac and available batches will be supplied in 
labeled 1.5 mL screw top cryovials at a concentration of 1.67 mg/mL and fill volume of 0.7 mL  
 
Storage 
CORVax will be stored in separate freezer boxes in a monitored -20°C ±10 freezer. Unopened drug product sterile 
vials should be stored in the packaging received from UbiVac in a secure, continuously temperature monitored and 
alarmed freezer in 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 Providence Medical Monitor. Drug product which experiences a temperature warmer than -
10°C remains suitable for clinical use provided all three of the following conditions are met: 
  
• 
Maximum one temperature excursion event to temperature greater (warmer) than -10°C.   
• 
Duration of the temperature excursion is not more than 3 hours.  
• 
Maximum temperature achieved is not more than 5°C.  
 
Drug product which experiences temperature excursions outside of these parameters should be immediately 
quarantined and reported to any member of the Providence Clinical team.  Providence (clinical team) will determine 
whether the affected product remains suitable for use or must be replaced.    
  
Stability 
Stability testing is ongoing and will continue during the duration of the clinical trial. Additional information about the 
product can be found in the Investigator’s Brochure (IB).  
 
Dose Preparation 
Please refer to the Study Pharmacy Manual for CORVax plasmid preparation and handling instructions. Briefly, the 
Investigational Drug Product is to be prepared according to the following directions:  
 
• 
Each vial contains 0.7 mL of available CORVax plasmid solution at dosing concentration of 1.67 mg/mL. 
• 
Total dose will be 0.8 +/- 0.15 mg (see Pharmacy manual for details). 
• 
On the day of treatment, remove the vials for each procedure from frozen storage. The research pharmacy will 
document time of removal (thaw start time) on an institutionally approved worksheet or the Investigational Product 
Formulation Worksheet.   


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• 
Remove the vials from the packaging and place at room temperature with space between the vials to allow free 
airflow; allow the vials to thaw completely at room temperature for approximately 5-10 minutes.   
• 
Inspect the vials to verify contents are completely thawed.  
• 
Thoroughly mix the vials by vigorous swirling or vortexing.   
• 
Use standard aseptic techniques. 
 
8.2.1 
Cohorts 1A & 2A - Intradermal CORVax only  
o 
Wipe the vial and cap with isopropyl alcohol and allow to completely dry.  
o 
Wipe a 1000 uL pipettor with isopropyl alcohol and allow to completely dry.  
o 
Using a sterile tip on the 1000 uL pipettor, gently pipette up and down ten times to mix the plasmid solution. 
o 
Using a sterile 1 mL syringe with a 25-gauge 5/8-inch needle and needle cap, withdraw 250 uL of plasmid 
solution per syringe, plus additional volume as needed to prime the syringe and ensure delivery of 250 
uL intradermal injection per syringe, (500 uL total). 
o 
Remove the needle and cap syringe(s). 
 
• 
Capped syringe(s) may be placed individually in a self-sealing plastic bag and stored in a 2-8ºC temperature 
controlled and monitored refrigerator until ready for use. 
• 
Discard unused portions of each vial into approved biohazard containers and dispose as per institutional 
requirements.  
• 
Syringe(s) may be transported from the pharmacy to the treatment area at room temperature.  
• 
The prepared formulation must be administered within 8 hours of removal from the freezer.  
 
 
8.3 pIL-12 (tavokinogene telseplasmid)  
How Supplied 
pIL-12 is formulated in phosphate buffered saline (PBS) for direct intradermal injection followed by in vivo EP. GLP-
grade pIL-12 is manufactured by Richter-Helm Biologics and vialed by UbiVac, and available batches will be 
supplied in labeled 1.25 mL screw top cryovials at a concentration of 3.3 mg/mL and fill volume of 0.3 mL.  
 
Storage  
Unopened vials of pIL-12 should be stored in the packaging received from UbiVac in a secure, continuously 
temperature monitored and alarmed freezer in 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 any member of the Providence Clinical team.  Drug 
product which experiences a temperature greater (warmer) than -10°C remains suitable for clinical use provided all 
three of the following conditions are met: 
  
• 
Maximum one temperature excursion event to temperature greater (warmer) than -10°C.   
• 
Duration of the temperature excursion is not more than 3 hours.  
• 
Maximum temperature achieved is not more than 5°C.  
 
Drug product which experiences temperature excursions outside of these parameters should be immediately 
quarantined and reported to any member of the Providence Clinical team.  Providence (clinical team) will determine 
whether the affected product remains suitable for use or must be replaced.    
  
Stability 
Stability testing is ongoing and will continue during the duration of the clinical trial. Additional information about the 
product can be found in the Investigator’s Brochure (IB).  
 
Dose Preparation Steps  
Please refer to the Study Pharmacy Manual for pIL-12 preparation and handling instructions Briefly, pIL-12 is to 
be prepared according to the following directions:  
 
• 
Each vial contains 0.3 mL of available pIL-12 solution at dosing concentration of 3.3 mg/mL. 
• 
Total dose will be 0.8 +/- 0.15 mg (see Pharmacy manual for details). 


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• 
On the day of treatment, remove the vials for each procedure from frozen storage. The site may choose to 
document the time of removal (thaw start time) on the Investigational Product Formulation Worksheet or an 
institutionally approved worksheet.   
• 
Remove the vials from the packaging and place at room temperature with space between the vials to allow free 
airflow; allow the vials to thaw completely at room temperature for approximately 5-10 minutes.   
• 
Inspect the vials to verify contents are completely thawed.  
• 
Thoroughly mix the vials by vigorous swirling or vortexing.   
• 
Use standard aseptic techniques:  
 
8.3.1 
Cohorts 1B & 2B - Intradermal CORVax + pIL-12 
o 
Wipe the vial and cap with isopropyl alcohol and allow to completely dry.  
o 
Wipe a 1000 uL pipettor with isopropyl alcohol and allow to completely dry.  
o 
Using a sterile tip on the 1000 uL pipettor, gently pipette up and down ten times to mix the plasmid solution. 
o 
Pipette 600 uL of CORVax into 300 uL pIL-12. 
o 
Gently pipette up and down ten times to mix the CORVax + pIL-12 plasmid mix. 
o 
Using a sterile 1 mL syringe with a 25-gauge 5/8-inch needle and needle cap, withdraw 375 uL of plasmid 
mix per syringe, plus additional volume as needed to prime the syringe and ensure delivery 375 uL 
intradermal injection per syringe, (750 uL total). 
o 
Remove the needle and cap syringe(s). 
 
• 
Capped syringe(s) may be placed in a self-sealing plastic bag and store in a 2-8ºC temperature controlled and 
monitored refrigerator until ready for use.  
• 
Discard unused portions of each vial into approved biohazard containers and dispose as per institutional 
requirements.  
• 
Syringe(s) may be transported from the pharmacy to the treatment area at room temperature.  
• 
The prepared formulation must be administered within 8 hours of removal from the freezer.  
 
 
8.4 Electroporation: IGEA CLINIPORATOR® with IGEA Applicator  
CLINIPORATOR® is a medical device for electroporation.  
 
This device shall be operated by trained medical/scientific staff who received specific training and instructed on 
electroporation and on the correct use of the device.   
 
• 
Wear surgical gloves made of insulating material when delivering pulses and while holding the electrodes. 
Gloves' electrical insulation is sufficient to avoid possible electrical effects on the operator that might 
produce small electrical shocks or muscle contraction due to treatment's voltage and current, and possible 
harm to the subject as a consequence. 
• 
Do not touch the electrode or the bushes of the handle with your fingers during the treatment. 
• 
To avoid risks of infection for the operators, the electrode must be handled with extreme caution. Avoid 
contact with the pointed needles. 
 
Electroporation is a physical phenomenon occurring in the cell membrane as cells are exposed to an electric 
field with proper characteristics. CLINIPORATOR® delivers voltage pulses based on standard parameters or as 
specified by the operator, which are then applied to the subject using the approved type of electrodes. 
The potential difference due to the pulses creates an electric field which acts on the cell membrane and induces 
an alteration which displays at macroscopic level an increased permeability of the membrane. Molecules that 
normally do not go past the cell membrane either in diffusion or active transport, after electroporation can reach 
the intracellular environment. 
 
Electroporation makes it possible, or rather increases the therapeutic effects of injected drugs, by temporarily 
increasing the cell membrane’s permeability enabling the cells to absorb the injected substances. 
 
In this study the electroporation is the basis for Electro-Gene-Transfer (EGT) to introduce DNA molecules into 
the cells. The device shall not be used for different purposes other than those intended. 
 


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The CLINIPORATOR® is a medical electroporation (EP) device system that consists of two main components:  
 
1. The IGEA Electroporation System that generates electric pulses, which includes the PC Panel, the Generator 
and the Foot Pedal.  
 
2. The IGEA Sterile Applicator - Model L-30-ST ("Applicator") containing an 8 needle array (2 rows of 4 needles 
in each row).  This needle array delivers electrical pulses which enable uptake of the vaccine which was 
intradermally injected with a standard syringe as outlined in Section 8.3. 
 
 
The Applicator contains an eight needle array with a 4.7 mm distance between the two rows of needles and 3.2 mm 
distance between the needles in each row. The needle length is 30 mm and the needle insertion depth can be adjusted 
by the user; penetration depth can be preset and locked in steps of 5mm up to a maximum of 30 mm.  For this 
procedure, the first lock of a 5mm penetration depth will be used. 
 
The  CLINIPORATOR® is only for use with the IGEA Applicator and associated cable assembly. The IGEA Applicator 
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. The 
CLINIPORATOR® should not be used near MRI equipment and RFID systems should not be used near the 
CLINIPORATOR® when it is in operation. Care should be taken to ensure that the device is not used in the vicinity of 
flammable anesthetics. The study staff and monitors should also check the study device supplies to ensure a sufficient 
amount of study Applicators and cable assemblies are on hand for active subjects and that the supplies are not expired.  
 
Storage Conditions for CLINIPORATOR® 
Room temperature from -20 to 50 °C. 
Relative humidity from 10% to 90%. 
Atmospheric pressure from 500 to 1060 hPa. 
 
Storage Conditions for applicator 
The electrode is supplied in a sterile package. It should be kept in a dry, clean place, away from heat sources and 
in compliance with the following ambient conditions: Temperature: 10°C - 40°C. Sterility is guaranteed until the 
expiry date printed on the package, provided that the double package remains intact. 
 
Additional details regarding handling of the device are provided in the  CLINIPORATOR®  User Manual.  
 
 
8.4.1 
All Cohorts - Intradermal EP 
Directly following intradermal injection of the plasmid solution using a standard syringe following SOC practices 
for intradermal vaccine administration, the EP applicator will be applied at the appropriate depth for intradermal 
EP (see Section 8.5.1 for instructions), such that the electrodes span the plasmid injection site of two adjacent 
blebs. The applicator will be connected to the power supply and upon user activation of the attached Foot Switch, 
eight pulses at a field strength (E+) of 400 V/cm and pulse width of 10 ms at 300 millisecond intervals will be 
administered. The EP administration is anticipated to be completed in less than 1 minute. No vaccination or EP 
administration should be administered in the left arm.  
 
 
8.5 Plasmid Injection followed by Electroporation (EP) 
Participants will be treated in one of four study cohorts:  
 
• 
All treatment will be delivered in the outpatient setting. 
 
• 
Vaccination is delivered to right or left buttocks over the dorsogluteal muscle.  
 
• 
For day 30 boost dose, any prior AEs must have resolved to grade 1 or lower as a condition of treatment.  
 
• 
Each vaccination consists of two steps: intradermal injection of the plasmid solution in two divided doses of 
equal volume, following SOC practices for intradermal vaccine administration (akin to PPD skin test, with two 
adjacent blebs in this case, see Figure 3), followed by EP delivery directly over the two flattened blebs. 
 
 


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• 
Each EP complete electrical pulse delivery occurs in less than 3 seconds with total EP applicator skin contact 
time of less than 1 minute. 
 
 
Figure 3: (A) injection technique for two adjacent intradermal blebs (photo from previous study, 0.5 mL per bleb; 
volumes will be lower in the current study, either 0.25 mL or 0.375 mL per bleb). (B) IGEA applicator electrode 
configuration relative to two intradermal injection blebs; the applicator contains an eight-needle array with a 4.7 
mm distance between the two rows of needles and 3.2 mm distance between the needles in each row.  
 
 
 
 
Cohorts 1A & 2A: SARS-CoV-2 (S) protein plasmid DNA vaccine  
 
 
CORVax 
 
Day 1 
Intradermal: 0.8 mg of (S) protein plasmid in 500 uL.* 
*followed by CLINIPORATOR® electroporation (EP) - 8 pulses (pulse width 10 ms) of 400 V/cm. 
 
Day 30 
Intradermal: 0.8 mg of (S) protein plasmid in 500 uL.* 
* followed by CLINIPORATOR® electroporation (EP) - 8 pulses (pulse width 10 ms) of 400 V/cm. 
 
 
 
 
Cohorts 1B & 2B: SARS-CoV-2 (S) protein plasmid DNA vaccine + pIL-12   
CORVax + pIL-12 
 
Day 1 
Intradermal: 0.8 mg of (S) plasmid + 0.8 mg of pIL-12 (total volume 750 uL).* 
* followed by CLINIPORATOR® electroporation (EP) - 8 pulses (pulse width 10 ms) of 400 V/cm. 
 
Day 30 
Intradermal: 0.8 mg of (S) protein plasmid + 0.8 mg of pIL-12 (total volume 750 uL).* 
* followed by CLINIPORATOR® electroporation (EP) - 8 pulses (pulse width 10 ms) of 400 V/cm. 
 
 
  
 
8.5.1 
Clinical Administration Technique 
Once the treatment syringe has been prepared, the syringes may be transferred to the treatment area at room 
temperature.  The treatment syringe should be visually inspected prior to injection, checking that the solution is 
homogeneous. If the solution does not appear homogeneous, the plasmid should be discarded and new plasmid 
for treatment prepared.   
 
Prior to plasmid injection, local anesthetics such as 1% lidocaine may be injected around the planned injection 
site to obtain local anesthesia. The area should be clean and wiped dry of any excess liquid prior to electroporation 


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procedure. Alternative local anesthetics may be used as clinically indicated and deemed clinically optimal. 
Icepacks to cool and numb an area are also acceptable. No systemic anesthesia should be used and the device 
should not be used in a room where flammable anesthetics are being used or stored. In addition, participants may 
be given anxiolytics (e.g., lorazepam 0.5 to 1mg PO once), and/or analgesics (e.g., ibuprofen 400 to 800mg PO 
once or oxycodone 5mg PO once), per institutional standard practice prior to, or during, treatment by qualified 
personnel (clinical RN). The options as delineated for prophylactic medication use are on par with standard 
practice for routine office procedures, (such as a shave biopsy) and would not be considered as adverse events.  
As with routine office procedures, the use of premedication is infrequent and optional; and as such, we do not see 
this as an impediment to widespread use of this vaccine approach during a pandemic.  
 
General Principles: 
 
• 
The intradermal injection of the plasmid solution is delivered in two divided doses of equal volume, 
following SOC practices for intradermal vaccine administration, (akin to PPD skin test, with two 
adjacent blebs in this case, see Figure 3). Injection is performed prior to electroporation. 
• 
Electroporation (EP) must be co-localized at the site of the two adjacent flattened blebs from 
intradermal syringe injection, and should be done as soon as reasonably possible following 
injection.  
• 
The EP applicator should be preset and locked at the 5mm penetration depth. This depth is 
maintained by pressing the applicator flush to subject's skin during the electroporation procedure. 
• 
The anticipated total time of EP applicator contact with the subject's skin is less than 1 minute.  
• 
Detailed instructions are provided in the  CLINIPORATOR®  User Manual, which should be 
reviewed prior to the start of treatment. 
 
 
 
8.5.2 
Monitoring Plan on Day of Administration 
Participant vital signs will be measured twice every 30 minutes, starting within 10-15 minutes post vaccination. 
The study investigator will review vitals prior to release from clinic.  
 
8.5.3 
Cohorts 1A & 2A: CORVax 
1. Intradermal: injection of CORVax 0.8 mg in 500 uL, followed directly by EP (e.g. right or left 
buttocks over the dorsogluteal muscle); record pain score 5 minutes post. 
 
 
8.5.4 
Cohorts 1B & 2B: CORVax + pIL-12 
1. Intradermal: injection of CORVax + pIL-12 in 750 uL (0.8 mg in 500 uL of CORVax + 0.8 mg in 
250 uL of pIL-12), followed directly by EP (e.g. right or left buttocks over the dorsogluteal muscle); 
record pain score 5 minutes post. 
 
 
8.6 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 thereafter28. EP-associated pain assessment monitoring will be performed days 1 and 30 at 
the start of each treatment and 5 minutes after EP procedure. Only pain that persists >5 minutes after the end of EP 
procedure will be evaluated on numeric pain rating scale and documented as an AE per the CTCAE (active version). 
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" 29–32. 
 
 
8.7 Management of Clinical Toxicity 
Subjects will be monitored during and after vaccine injection and electroporation. Vital signs will be measured as 
specified in Section 8.5.2. Acetaminophen and/or an antihistamine (e.g., diphenhydramine) may be administered for 


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treatment-related reactions at the discretion of the investigator. As with any vaccine therapy, allergic reactions to dose 
administration are possible. Therefore, appropriate drugs and medical equipment to treat acute anaphylactic reactions 
must be immediately available, and study personnel must be trained to recognize and treat anaphylaxis.  There will 
be no dose modifications in this study. 
 
 
8.8 Reporting Product Complaints 
Any defects with the investigational product must be reported immediately to the OncoSec Medical Incorporated 
Clinical Development Department by the site with further notification to the site monitor. All defects will be 
communicated to OncoSec and investigated further with the Quality Assurance and Product Complaint Department. 
During the investigation of the product complaint, all investigational product must be stored at labeled conditions 
unless otherwise instructed.  OncoSec contact information for reporting product complaints:  
 
Email: kmalloy@oncosec.com 
Tel:  
+858.375.9989  
 
Mail: 
OncoSec Medical Incorporated 
Attn: Clinical Development – Re: Product Complaint  
24 N Main Street, Pennington NJ 08540 
 
 
 
9. IMMUNODYNAMIC BIOMARKERS 
9.1 
Immunologic Monitoring 
Blood sampling for plasmid expression levels and immune response measurements will occur on days 1, 2, 3, 15, 30, 
31, 32, 45, 60 and 90 of study. The main objectives of the monitoring will be to characterize both the antibody and 
cellular immune response to the pUMVC3-CORVax vaccine. The sites performing these studies will include the 
Earle A. Chiles Research Institute Laboratories, (Immune Monitoring Laboratory (IML), Molecular and Tumor 
Immunology Laboratory (MTI), Laboratory of Cancer Immunobiology (LCI) and Molecular Pathology Laboratories 
(MPL)) or outside vendors selected by the Principle Investigator and research team. Blood will be processed and 
cryopreserved for subsequent monitoring or flow cytometry with a panel of markers will be run the day blood is drawn. 
At a minimum the panels will include CD4, CD8, NK, and B cells. If NIAID or other grant resources become available 
additional monitoring is planned and may include CD4 T conventional, Treg, T memory, Ki-67, CD38, HLA-DR, CD40, 
ICOS, granzyme B, PD-1, TIM-3, LAG-3, 4-1BB, CTLA-4, OX40R, NKG2A, CD94, NKp46, NKG2D, NKp30, CD158e1, 
KIRc, CD158b, CD11b, CD15, CD33, CD54, CD80, CD83, CD86, PD-L1, PD-L2. Sorted immune cell subsets could 
also be submitted for RNA/DNA extraction and genome-wide CpG methylation by target-capture DNA library 
preparation and Illumina sequencing.   
9.2 
Neutralization assay  
Antibody neutralization of the SARS-CoV-2 will be assessed using a pseudotyped lentivirus expressing the SARS-
CoV-2 (S) protein and luciferase. Readout will be the ability of sera from vaccinated candidates to prevent infection of 
susceptible target cells. Alternatively, a surrogate viral neutralization test, reporting ability of sera to block hACE2R 
binding to spike will be performed. 
9.3 
Cytokines 
If grant support is available, serum cytokine profiling will be performed using the Quanterix Simoa platform evaluating 
systemic IL-12p70 as well as 35 additional cytokines including IFN-gamma, TNF-alpha, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-
8, IL-10, IL-17A and TGF-beta.  


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9.4 
T cell response 
SARS-CoV-2 (S) protein-specific cellular immune responses will be measured by cytokine-release assay for type I, 
type 2 and IL-17 cytokine responses using cytokine bead arrays. IFN-gamma positive responses will be assessed by 
interferon-gamma ELISA and either intracellular cytokine staining (ICS) or ELISPOT assay using unfractionated 
PBMC and peptide pools of epitopes considered to be dominant epitopes for the HLA expressed by the specific 
subject. If predicted HLA-binding epitopes fail to identify targets of immune response, peptide pools containing 15-
mer peptides overlapping by 11 amino acids will be explored. Our prediction is that the cytokine response to whole 
protein will be dominated by CD4+ T-cell response and that the response to overlapping peptides will comprise both 
CD4+ and CD8+ T-cell responses.  
9.5 
B cell response 
Analysis of antibody responses to SARS-CoV-2 spike (S) glycoprotein will be performed using Microaffinity proteomic 
(MAP) bead technology or ELISA. Bead arrays containing SARS-CoV-2 proteins will be used to assess IgM and the 
isotype of IgG responses that develop following vaccination. Humoral response will also be monitored by B-Cell 
ELISPOT evaluating PBMC for IgA, IgM, and IgG response to the COVID-19 S spike to determine the B cell response 
that has developed. 
9.6 
Coordinated humoral/cellular response 
Grant support is being requested to perform single-cell RNA sequencing at day 0, 15, 30, 45, 60 and 90. It is planned 
that paired αβ TCRseq and tandem BCRseq using the Archer Immunoverse platform will allow tracking of T and B 
cell clones and provide opportunities to assess whether dominant clones recognize epitopes of the SARS-CoV-2 spike 
protein. We have successfully used this technology to isolate tumor-reactive TCRs from peripheral blood of subjects 
on a cancer vaccine trial33. We postulate that persisting neutralizing Ab responses will result from a coordinated CD4, 
CD8 and B cell response to the SARS-CoV-2 spike (S) glycoprotein. 
9.7 
 Whole genome sequencing 
Whole genome sequencing will be performed to assess polymorphisms in immune-response related genes. It will also 
provide the HLA haplotypes. This information will be evaluated for relationships to the magnitude of the immune 
response to vaccination. The studies performed here, while only a small number of subjects and some of which are 
exploratory in nature, may provide insights into the apparently unique biology of this virus. We will also look for 
correlations with the depth and magnitude of response to vaccination. 
9.8 
Clinical Outcomes and Surveillance Database 
A coded, de-identified clinical database will be maintained by the study PI or clinical research as delegated by the 
study PI.  The database and codes key will be housed on a password and encryption protected network drive, only 
accessible to the study PI and delegated staff.  Participants will provide consent for inclusion in the longitudinal study 
database at enrollment.  Clinical data will be collected from time of enrollment to a minimum of five years clinical 
surveillance post completion of treatment, or death or loss to follow-up.  Such data will include but not be limited to: 
age at time of study, medications, medical and surgical history.   
 
10.  REGULATORY & REPORTING REQUIREMENTS 
10.1 Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) active version.  The CTCAE 
active version can be accessed from the CTEP home page (http://ctep.cancer.gov). 
 
10.2 Definitions 
Serious adverse event: 
A serious adverse drug or device experience is defined as any adverse drug or device experience occurring at any 


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dose or experience with the device that results in any of the following outcomes: Death, a life-threatening adverse 
drug or device experience, hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered a serious adverse drug or device experience when, 
based upon appropriate medical judgment, they may jeopardize the participant or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  
 
Unexpected adverse event:  
Any adverse drug or device experience, the specificity or severity of which is not consistent with the current investigator 
brochure; or, if an investigator brochure is not required or available, the specificity or severity of which is not consistent 
with the risk information described in the general investigational plan or elsewhere in the current application, as 
amended.  
 
Associated with the use of the drug / device / intervention:  
There is a reasonable possibility that the experience may have been caused by the drug or device. 
 
Disability: 
A substantial disruption of a person's ability to conduct normal life functions. 
 
Life-threatening adverse event: 
Any adverse drug or device experience that places the participant or subject, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a 
more severe form, might have caused death. 
 
Unanticipated Problem 
An unanticipated problem is an adverse event that is (i) unexpected; (ii) serious; and (iii) felt by the investigator to be 
possibly, probably, or definitely related to the research intervention. Only adverse events that meet this definition need 
be reported to the IRB. 
 
For more information on the definition of an unanticipated problem and reporting requirement, consult the current 
PH&S AE Guidelines published on the IRB website (http://phsnet.phsor.org/institutional_review_board). 
  
10.3 Adverse Event Reporting 
PSJH IRB  
An unanticipated event that is serious and definitely or probably caused by the study treatment (drugs or device) will 
be reported to the IRB in accordance with their guidelines and within their timelines. 
 
FDA Reporting  
The Principal Investigator is responsible for determining whether or not the suspected adverse reaction meets the 
criteria for expedited reporting in accordance with Federal Regulations (21 CFR §312.32).  A suspected adverse 
reaction must be both serious and unexpected in order to meet the reporting requirements.   
 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the investigator 
brochure, the device user manual, or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure or device user manual is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application, as amended. 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the investigator, it 
results in any of the following outcomes: Death, a life-threatening adverse event, hospitalization or prolongation of 
existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
 
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after the Investigator 
determines that the suspected adverse reaction qualifies for reporting (21 CFR 312.32(c)(1)).  
 


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Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no later than 7 calendar 
days after the Investigator’s initial receipt of the information (21 CFR 312.32(c)(2)).  
 
Any relevant additional information that pertains to a previously submitted IND safety report will be submitted to FDA 
as a Follow-up IND Safety Report without delay, as soon as the information is available (21 CFR 312.32(d)(2)).  
 
Any potentially vaccine-related immune-mediated medical condition (see Appendix 2) that occurs will be considered 
unexpected. Expedited reporting requirements (as outlined in 21 CFR 312.32) will be followed for any adverse event 
assessed as a serious and unexpected suspected adverse reaction (SUSAR).  
 
10.4 Continuing Review and Final Reports 
An annual progress report (continuing review) will be submitted to the IRB for the duration of the study. A final report 
to the IRB will be submitted at the summation of the study. 
 
All IND annual reports, clinical trial reports, and clinical trial report addenda submitted to the FDA will include tabulated 
summaries of available adverse event data for potentially immune-mediated medical conditions reported during the 
trial, categorized by MedDRA term. These summaries will include any conditions reported during the trial that match 
the terms listed in Appendix 2, as well as any other potentially immune-mediated medical conditions (pIMMCs) 
reported during the trial that do not appear on the list in Appendix 2. For each adverse event included in the summaries, 
a case narrative will be provided, along with an assessment of the seriousness of the event and causal relationship to 
study vaccine, as required by 21 CFR 312.32.  
 
Collection of MAAE data beyond 6 months after the last study vaccination will not delay submission of clinical trial 
reports and initiation of subsequent clinical trials, and final analyses of MAAEs may be submitted in clinical trial report 
addenda. 
 
The safety analysis in the final clinical study report will include the number and proportion of subjects in each cohort 
reporting 1) each solicited AE of any grade through seven days following any dose and each dose, 2) each solicited 
AE grade 3 and greater within seven days following any dose and each dose, 3) unsolicited AEs of any grade reported 
at a minimum through 28 days following dose 2, 4) unsolicited AEs grade 3 and greater reported at a minimum through 
28 days following dose 2, 5) SAEs within 28 days following dose 2, 6) SAEs, MAAEs, and pIMMCs reported through 
one year following dose 2. In addition, it will include the number and proportion of subjects in each cohort of each 
category of AE that the investigator assessed as related. 
 
10.5 Protocol Modifications and Amendments 
Once the protocol has been approved by the IRB, any changes to the protocol must be documented in the form of an 
amendment.  The amendment must be approved by IRB prior to implementation. If it becomes necessary to alter the 
protocol to eliminate an immediate hazard to Participants, an amendment may be implemented prior to IRB approval.  
In this circumstance, however, the Investigator must then notify the IRB in writing within five (5) working days after 
implementation. 
 
10.6 Record Retention 
The Principal Investigator is required to maintain adequate records of the disposition of the drug, including dates, 
quantity, and use by subjects, as well as written records of the disposition of the drug when the study ends. The 
Principal Investigator is required to prepare and maintain adequate and accurate case histories that record all 
observations and other data pertinent to the investigation on each individual administered the investigational drug or 
employed as a control in the investigation. Case histories include the case report forms and supporting data including, 
for example, signed and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall document 
that informed consent was obtained prior to participation in the study. Study documentation includes all CRFs, data 
correction forms or queries, source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, CHR correspondence and approval, signed participant 
consent forms). Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. In accordance with 
FDA regulations, the investigator shall retain records for a period of 2 years following the date a marketing application 
is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the 


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application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified. 
 
10.7 Oversight and Monitoring Plan 
Oversight of participant safety will include review of adverse events as well as study progress and outcomes.  Adverse 
events, outcomes, and recruitment and retention of Participants will be reviewed on a weekly basis by the PI, research 
nurse, and data coordinator.  Protocol deviations are reviewed monthly at the Providence Cancer Institute’s Quality 
Assurance Committee meetings (monthly). Study monitoring activities (Quality Control Reviews) are performed by 
clinical research staff members who have completed specialized training in study monitoring procedures and human 
subjects’ protections.  Individuals who perform study monitoring activities do not report to Principal Investigators or 
research scientists and may not monitor studies for which they have direct responsibility.  Results of study monitoring 
activities will be reported to applicable study personnel, Clinical Research Program Managers and Quality 
Assurance.  Study monitoring activities are conducted regularly and include (but are not limited to) review and 
verification of the following: 
 
• 
Eligibility 
• 
Informed Consent process 
• 
Adherence to protocol treatment plan 
• 
Case Report Forms (CRFs) 
• 
Source Documentation 
• 
Adverse Events 
• 
Regulatory Reporting 
 
10.8 Quality Assurance 
Quality Assurance (QA) personnel review study monitoring reports and if necessary, determine follow-up actions to 
resolve significant findings. QA has the authority to request immediate corrective action if significant participant safety 
issues are identified.  QA will track and trend results from study monitoring reports as well as associated corrective 
and preventive actions.  A QA summary report will be provided to the IRB at the time of continuing review. QA 
personnel do not have a direct reporting relationship to the Principal Investigator and are not responsible for enrollment 
or coordination of care for study participants. 
 
10.9 Case Report Forms (CRFs) 
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and accurate participant case 
histories with observations and data pertinent to the study.  Study specific Case Report Forms (CRFs) will document 
safety and treatment outcomes for safety monitoring and data analysis.  All study data will be entered into Velos 
eResearch via eCRFs.  The Clinical Research Associate (CRA) will complete the CRFs as soon as possible upon 
completion of the study visit; the Investigator will review and approve the completed CRFs. The information collected 
on CRFs shall be identical to that appearing in original source documents.  Source documents will be found in the 
participant’s electronic medical records.  All printed source documentation should be kept in separate research folders 
for each participant. 
 
 
11. STATISTICAL CONSIDERATIONS 
11.1 Sample Size and Statistical Analysis 
Sample size: 36 participants will be enrolled and assessed for safety in one of four study cohorts (9 participants per 
cohort). Participants who enroll but do not complete therapy for reasons other than DLT may be replaced.   
   
Statistical analysis: The safety evaluation will be based on the treated population, which includes all participants who 
receive any investigational product. Demographic and baseline characteristics will be summarized with means, 
medians, standard deviations, ranges or percentages. Safety will be summarized by the percentage of participants 
with adverse events, with grading according to the Common Terminology Criteria for Adverse Events (CTCAE, active 
version).   
 


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11.2 Participant Accrual 
We do not foresee barriers to accrual of healthy adult volunteers, in light of the recent Seattle experience with rapid 
accrual of healthy volunteers to a comparable SARS-CoV-2 phase I vaccine study. Individuals will not be reimbursed 
for participation in this study. 
 
 
 
 
 
 


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APPENDIX 1: Toxicity Grading Scale  
 
Adapted from “FDA Guidance for Industry 2005D-0155: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials” accessible at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/toxicity-grading-scale-healthy-adult-and-adolescent-volunteers-enrolled-
preventive-vaccine-clinical 
 
Tables for Clinical Abnormalities  
Local Reaction to 
Injectable Product  
Mild (Grade 1)  
Moderate (Grade 2)  
Severe (Grade 3)  
Potentially Life 
Threatening (Grade 4)  
Pain  
Does not interfere 
with activity  
Repeated use of non- narcotic 
pain reliever > 24 hours or 
interferes with activity  
Any use of narcotic 
pain reliever or 
prevents daily activity, 
> 72 hours  
Emergency room (ER) visit 
or hospitalization  
Tenderness  
Mild discomfort to 
touch  
Discomfort with movement  
Significant discomfort 
at rest > 72 hours 
ER visit or hospitalization  
Erythema/Redness *  
2.5 – 5 cm  
5.1 – 10 cm  
> 10 cm > 72 hours  
Necrosis or exfoliative 
dermatitis  
Induration/Swelling **  
2.5 – 5 cm and does 
not interfere with 
activity  
5.1 – 10 cm or interferes with 
activity  
> 10 cm or prevents 
daily activity > 72 
hours 
Necrosis  
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a 
continuous variable.  
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement.   
Vital Signs *  
Mild (Grade 1)  
Moderate (Grade 2)  Severe (Grade 3)  
Potentially Life   
Threatening (Grade 4)  
Fever (°C) ** (°F) **  
38.0 – 38.4;                
100.4 – 101.1  
38.5 – 38.9;             
101.2 – 102.0  
39.0 – 40;             
102.1 – 104  
symptomatic for >24 
> 40 > 104  
Tachycardia - beats per 
minute  
101 – 115  
116 – 130  
> 130 for > 24 hours 
and symptomatic 
ER visit or hospitalization for 
arrhythmia  
Bradycardia - beats per 
minute***  
50 – 54  
45 – 49  
< 45 for > 24 hours 
and symptomatic 
ER visit or hospitalization for 
arrhythmia  
Hypertension (systolic) - mm 
Hg  
141 – 150  
151 – 155  
> 155 for > 48 hours 
and symptomatic 
ER visit or hospitalization for 
malignant hypertension  
Hypertension (diastolic) - mm 
Hg  
91 – 95  
96 – 100  
> 100 for > 48 hours 
and symptomatic 
ER visit or hospitalization for 
malignant hypertension  
Hypotension (systolic) – mm 
Hg  
85 – 89  
80 – 84  
< 80 and symptomatic ER visit or hospitalization for 
hypotensive shock  
Respiratory Rate – breaths per 
minute  
17 – 20  
21 – 25  
> 25 and symptomatic Intubation  
* Subject should be at rest for all vital sign measurements. 
** Oral temperature; no recent hot or cold beverages or smoking. 
*** When resting heart rate is between 60 – 100 beats per minute. Use clinical judgement when characterizing bradycardia among 
some healthy subject populations, for example, conditioned athletes.  
 


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Systemic 
(General)  
Mild (Grade 1)  
Moderate (Grade 2)  
Severe (Grade 3)  
Potentially Life 
Threatening (Grade 4)  
Nausea/vomiting  
No interference 
with activity or 1 – 2 
episodes/24 hours  
Some interference with 
activity or > 2 episodes/24 
hours  
Prevents daily activity and 
requires outpatient IV hydration  
ER visit or hospitalization 
for hypotensive shock  
Diarrhea  
2 – 3 loose stools or < 
400 gms/24 hours  
4 – 5 stools or 400 – 800 
gms/24 hours  
6 or more watery stools/24 hours 
and requires outpatient IV 
hydration  
ER visit or hospitalization  
Headache  
No interference with 
activity  
Repeated use of non- 
narcotic pain 
reliever > 24 hours or some 
interference with activity  
Significant; any use of narcotic 
pain reliever or prevents daily 
activity  
ER visit or hospitalization  
Fatigue  
No interference with 
activity  
Some interference with 
activity  
Significant; prevents daily 
activity lasting > 48 hours 
ER visit or hospitalization  
Myalgia  
No interference with 
activity  
Some interference with 
activity  
Significant; prevents daily 
activity lasting > 72 hours 
ER visit or hospitalization  
 
Systemic Illness  
Mild (Grade 1)  (Moderate (Grade 2)  
Severe (Grade 3)  
Potentially Life 
Threatening 
(Grade 4)  
Illness or clinical adverse event 
(as defined according to 
applicable regulations)  
No interference 
with activity  
Some interference with 
activity not requiring medical 
intervention  
Prevents daily activity and 
requires medical 
intervention  
ER visit or 
hospitalization  
 
Tables for Laboratory Abnormalities  
Serum *  
Mild (Grade 1)  Moderate (Grade 2)  Severe (Grade 3)  
Potentially Life 
Threatening 
(Grade 4)**  
Sodium – Hyponatremia mEq/L  
132 – 134  
130 – 131  
125 – 129  
< 125  
Sodium – Hypernatremia mEq/L  
144 – 145  
146 – 147  
148 – 150  
> 150  
Potassium – Hyperkalemia mEq/L  
5.1 – 5.2  
5.3 – 5.4  
5.5 – 5.6  
> 5.6  
Potassium – Hypokalemia mEq/L  
3.5 – 3.6  
3.3 – 3.4  
3.1 – 3.2  
< 3.1  
Glucose – Hypoglycemia mg/dL  
65 – 69  
55 – 64  
45 – 54  
< 45  
Glucose – Hyperglycemia Fasting – mg/dL 
Random – mg/dL  
100 – 110  
110 – 125  
111 – 125    
126 – 200  
>125  
 >200  
Insulin requirements 
or hyperosmolar 
coma  
Blood Urea Nitrogen BUN mg/dL  
23 – 26  
27 – 31  
> 31  
Requires dialysis  
Creatinine – mg/dL  
1.5 – 1.7  
1.8 – 2.0  
2.1 – 2.5  
> 2.5 or requires 
dialysis  
Calcium – hypocalcemia mg/dL  
8.0 – 8.4  
7.5 – 7.9  
7.0 – 7.4  
< 7.0  
Calcium – hypercalcemia mg/dL  
10.5 – 11.0  
11.1 – 11.5  
11.6 – 12.0  
> 12.0  
Magnesium – hypomagnesemia mg/dL  
1.3 – 1.5  
1.1 – 1.2  
0.9 – 1.0  
< 0.9  
Phosphorous – hypophosphatemia mg/dL  
2.3 – 2.5  
2.0 – 2.2  
1.6 – 1.9  
< 1.6  
CPK – mg/dL  
1.25 – 1.5 x 
ULN***  
1.6 – 3.0 x ULN  
3.1 –10 x ULN  
> 10 x ULN  
Albumin – Hypoalbuminemia g/dL  
2.8 – 3.1  
2.5 – 2.7  
< 2.5  
--  
Total Protein – Hypoproteinemia g/dL  
5.5 – 6.0  
5.0 – 5.4  
< 5.0  
--  


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Alkaline phosphate – increase by factor  
1.1 – 2.0 x ULN  2.1 – 3.0 x ULN  
 3.1–10 xULN  
> 10 x ULN  
Liver Function Tests –ALT, AST increase by 
factor  
1.1 – 2.5 x ULN  2.6 – 5.0 x ULN  
5.1 – 10 x ULN  
> 10 x ULN  
Bilirubin – when accompanied 
by any increase in Liver Function Test increase 
by factor  
1.1 – 1.25 x ULN  1.26 – 1.5 x ULN  
1.51 – 1.75 x ULN  > 1.75 x ULN  
Bilirubin – when Liver Function Test is normal; 
increase by factor  
1.1 – 1.5 x ULN  1.6 – 2.0 x ULN  
2.0 – 3.0 x ULN  
> 3.0 x ULN  
Cholesterol  
201 – 210  
211 – 225  
> 226  
---  
Pancreatic enzymes – amylase, lipase  
1.1 – 1.5 x ULN  1.6 – 2.0 x ULN  
2.1 – 5.0 x ULN  
> 5.0 x ULN  
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters at the time 
of the study. Institutional normal reference ranges should be provided to the investigator for final grade assignment.  
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the laboratory 
abnormalities as Potentially Life Threatening (Grade 4). For example. a low sodium value that falls within a grade 3 parameter (125-
129 mE/L) should be recorded as a grade 4 hyponatremia event if the subject had a new seizure associated with the low sodium 
value.  
*** “ULN” is the upper limit of the normal range.   
Hematology *  
Mild (Grade 1)  
Moderate (Grade 2)  Severe (Grade 3)  
Potentially Life 
Threatening (Grade 4)  
Hemoglobin (Female) - gm/dL  
11.0 – 12.0  
9.5 – 10.9  
8.0 – 9.4  
< 8.0  
Hemoglobin (Female) 
change from baseline value - 
gm/dL  
Any decrease – 1.5  1.6 – 2.0  
2.1 – 5.0  
> 5.0  
Hemoglobin (Male) - gm/dL  
12.5 – 13.5  
10.5 – 12.4  
8.5 – 10.4  
< 8.5  
Hemoglobin (Male) 
change from baseline value – 
gm/dL  
Any decrease – 1.5  1.6 – 2.0  
2.1 – 5.0  
> 5.0  
WBC Increase - cell/mm
3  
10,800 – 15,000  
15,001 – 20,000  
20,001 – 25, 000  
> 25,000  
WBC Decrease - cell/mm
3  
2,500 – 3,500  
1,500 – 2,499  
1,000 – 1,499  
< 1,000  
Lymphocytes Decrease - cell/mm
3 750 – 1,000  
500 – 749  
250 – 499  
< 250  
Neutrophils Decrease - cell/mm
3  1,500 – 2,000  
1,000 – 1,499  
500 – 999  
< 500  
Eosinophils - cell/mm
3  
650 – 1500  
1501 - 5000  
> 5000  
Hypereosinophilic  
Platelets Decreased - cell/mm
3  
125,000 – 140,000  
100,000 – 124,000  
25,000 – 99,000  
< 25,000  
PT – increase by factor 
(prothrombin time)  
1.0 – 1.10 x ULN**   1.11 – 1.20 x ULN  
1.21 – 1.3 x ULN  
> 1.3 ULN  
PTT – increase by factor (partial 
thromboplastin time)  
1.0 – 1.2 x ULN  
1.21 – 1.4 x ULN  
1.41 – 1.5 x ULN  
> 1.5 x ULN  
Fibrinogen increase - mg/dL  
400 – 500  
501 – 600  
> 600  
--  
Fibrinogen decrease - mg/dL  
150 – 200  
125 – 149  
100 – 124  
< 100 or associated with 
gross bleeding or 
disseminated intravascular 
coagulation (DIC)  
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. 
Institutional normal reference ranges should be provided to the investigator for final grade assignment.  
** “ULN” is the upper limit of the normal range.  


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Urine *  
Mild (Grade 1)  
Moderate (Grade 2)  Severe (Grade 3)  
Potentially Life 
Threatening (Grade 4)  
Protein  
Trace  
1+  
2+  
Hospitalization or dialysis  
Glucose  
Trace  
1+  
2+  
Hospitalization for 
hyperglycemia  
Blood (microscopic) – red blood 
cells per 
high power field (rbc/hpf)  
1 - 10  
11 – 50  
> 50 and/or gross 
blood  
Hospitalization or packed 
red blood cells (PRBC) 
transfusion  
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. 
Institutional normal reference ranges should be provided to demonstrate that they are appropriate.  
 
 


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APPENDIX 2: Medically Attended Adverse Events - pIMMCs 
 
List of Potentially Immune-Mediated Medical Conditions (pIMMCs) 
 
 
Gastrointestinal disorders 
Celiac disease 
Crohn’s disease 
Ulcerative colitis 
Ulcerative proctitis 
 
Liver disorders 
Autoimmune cholangitis 
Autoimmune hepatitis 
Primary biliary cirrhosis 
Primary sclerosing cholangitis 
 
Metabolic diseases 
Addison’s disease 
Autoimmune thyroiditis (including Hashimoto thyroiditis) 
Diabetes mellitus type I 
Grave's or Basedow’s disease 
 
Musculoskeletal disorders 
Antisynthetase syndrome 
Dermatomyositis 
Juvenile chronic arthritis (including Still’s disease) 
Mixed connective tissue disorder 
Polymyalgia rheumatic 
Polymyositis 
Psoriatic arthropathy 
Relapsing polychondritis 
Rheumatoid arthritis 
Scleroderma, including diffuse systemic form and CREST syndrome 
Spondyloarthritis, including ankylosing spondylitis, reactive arthritis (Reiter's 
Syndrome) and undifferentiated spondyloarthritis 
Systemic lupus erythematosus 
Systemic sclerosis 
 
Neuroinflammatory disorders 
Acute disseminated encephalomyelitis, including site specific variants (e.g., non-infectious encephalitis, 
encephalomyelitis, myelitis, radiculomyelitis) 
Cranial nerve disorders, including paralyses/paresis (e.g., Bell’s palsy) 
Guillain-Barré syndrome, including Miller Fisher syndrome and other variants 
Immune-mediated peripheral neuropathies and plexopathies, including 
chronic inflammatory demyelinating polyneuropathy, multifocal motor 
neuropathy and polyneuropathies associated with monoclonal gammopathy 
Multiple sclerosis 
Narcolepsy 
Optic neuritis 
Transverse myelitis 
Myasthenia gravis, including Eaton-Lambert syndrome 
 
Skin disorders 
Alopecia areata 
Autoimmune bullous skin diseases, including pemphigus, pemphigoid and 
dermatitis herpetiformis 
Cutaneous lupus erythematosus 


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Erythema nodosum 
Morphoea 
Lichen planus 
Psoriasis 
Rosacea 
Sweet’s syndrome 
Vitiligo 
 
Vasculitides 
Large vessels vasculitis including: giant cell arteritis such as Takayasu's arteritis and temporal arteritis 
Medium sized and/or small vessels vasculitis including: polyarteritis nodosa, Kawasaki's disease, microscopic 
polyangiitis, Wegener's granulomatosis, Churg–Strauss syndrome (allergic granulomatous angiitis), Buerger’s disease 
thromboangiitis obliterans, necrotizing vasculitis and anti-neutrophil cytoplasmic antibody (ANCA) positive vasculitis 
(type unspecified), Henoch- Schonlein purpura, Behcet's syndrome, leukocytoclastic vasculitis 
 
Others 
Antiphospholipid syndrome 
Autoimmune hemolytic anemia 
Autoimmune glomerulonephritis (including IgA nephropathy, 
glomerulonephritis rapidly progressive, membranous glomerulonephritis, membranoproliferative glomerulonephritis, and 
mesangioproliferative glomerulonephritis) 
Autoimmune myocarditis/cardiomyopathy 
Autoimmune thrombocytopenia 
Goodpasture syndrome 
Idiopathic pulmonary fibrosis 
Pernicious anemia 
Raynaud’s phenomenon 
Sarcoidosis 
Sjögren’s syndrome 
Stevens-Johnson syndrome 
Uveitis 
 


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