Additional information on the investigational device is available in the manual. 1.3 Preclinical Data 1.3.1 VGX -3100 Preclinical Data DNA plasmids for HPV -16 (pCon16E6E7) and HPV -18 (pCon18E6E7) have been studied for pre-clinical expression and immunogenicity. Preclinical GLP toxicology and biodi stribution studies with VGX -3100 have demonstrated an acceptable safety profile in New Zealand white rabbits (Refer to INO -3112 IB for details) . 1.3.2 INO -9012 Preclinical Data IL-12, a dendritic cell (DC) -produced cytokine, is a strong stimulator of NK cells as well as of T lymphocyte activity. IL -12 supports the differentiation of antigen specific CD4 T cells to produce Th1 cytokines including IFN-gamma and triggers the expansion of antigen specific CD8 T cells to express cytotoxic mediators, such as granzyme B /perforin [20-23] . The use of IL -12 DNA (e.g. INO-9012) as an immune adjuvant has proven effective at improving immune priming ex vivo as well as in animal models [24-26]. See Section 4 of the INO-3112 I B for details . 20 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol 1.4 Clinical Data 1.4.1 VGX -3100 Clinical Data VGX- 3100 has been tested in 2 Phase I clinical trials ( HPV-001 and HPV-002) in adult females post- surgical or ablative treatment of grade 2 or 3 cervical intraepithelial neoplasia (CIN) to evaluate safety and immunogenicity [12]. S afety data showed only mild to moderate Grade 1 and 2 adverse events, mainly injection site local reactions and non-clinically significant laboratory abnormalities. There were no serious adverse events attributed to treatment in any of the subjects enrolled and no study subjects discontinued early. VGX- 3100 is being evaluated in an ongoing Phase II study in women with high grade CIN (HPV -003). VGX- 3100 was immunogenic and effi cacious against CIN 2/3 without any significant safety concern s (Refer to INO-3112 IB for details) . 1.4.2 INO -9012 Clinical Data The safety profile associated with IM administration of IL -12 plasmid DNA alone or followed by EP has been acceptable in previous clinical studies. Clinical results from three different studies substantiate the safety and tolerability profile of IL -12 plasmid DNA. IL -12 plasmid DNA has been used in several cohorts in the following four phase I clinical protocols. Protocol # Co-administered with # subjects received IL -12 DNA HVTN-060 HIV-1 gag p37 80 HVTN-063 HIV-1 gag p37 30 HVTN-070 PENNVAX®-B (gag, pol, env) 30 HVTN-080 PENNVAX®-B (gag, pol, env) 30 IL-12 DNA was delivered without EP in HVTN -060, - 063 and -070 but was followed by EP in HVTN-080. In the protocol HVTN-080, PENNVAX®-B or placebo were delivered via IM injection followed by electroporation with the CELLECTRA®-5P device in 48 healthy volunteers. The regimen consisted of 3 mg of PENNVAX®-B with or without plasmid encoding IL -12 at months 0, 1 and 3. This study establishe d that a highly engineered DNA vaccine delivered intramuscularly followed by EP can induce frequent and robust T-cell responses in humans. In summary of above clinical studies, no pattern of systemic AEs emerged, and no SAEs related to the study products were observed. The pla smid DNA vaccine co-administered with IL-12 plasmid DNA as a cytoki ne adjuvant were well -tolerated (Refer to INO-3112 IB for details ). 1.4.3 CELLECTRA® Device Clinical Use Clinical Experience with Inovio Plasmid DNA -based Immunotherapy Delivered by Electroporati on using CELLECTRA® device: The underlying basis for all studies of plasmid DNA vaccines is the fairly substantial safety database that exists for the varied plasmid DNA vaccine candidates that have now been studied in humans. The plasmid DNA platform has been utilized for vaccine candidates for a variety of 21 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol disease indications and infectious agents (e.g., HIV, HPV, Influenza, SARS, West Nile virus, Ebola among others) in addition to plasmid cytokine adjuvants such as IL- 2, IL -12 and IL-15. Four separate GL P toxicology and biodistribution studies have been performed for eight additional plasmid DNA vaccine candidates developed by Inovio Pharmaceuticals, Inc. with identical backbones delivered by electroporation yielding similar toxicity and biodistribution profiles. As of April 7 , 2015, 587 human subjects had been treated with electroporation using the Inovio CELLECTRA ® device in more than 14 different studies. The total includes more than 1300 injections (IM or ID) of DNA followed by EP and approximately 186 injections of placebo followed by EP (refer to Investigator Brochure for details ) without any clinically significant safety issues . 1.5 Dose Rationale and Risk/Benefits 1.5.1 Dose Rationale The doses selected are based on previous human experience and preclinical d ata with VGX -3100 and other DNA vaccines. A total dose of 6 mg VGX -3100 DNA has been selected for this study based on the safety and immunogenicity data generated in the HPV -001 study, where 6 mg of DNA were delivered IM followed by EP, which showed trends toward higher response rates and magnitudes of IFN-γ ELISpot responses in the high dose cohort compared to the low (0.6 mg) and mid-dose (2 mg) cohorts (Table 1.1) without significant safety issues [12]. This dose -trend was consistent with prior expectations , suggest ing that it may be a real effect rather than random variation. Adverse events from previous human studies with closely related DNA plasmid product s have been limited to injection site pain from the injection and electroporation procedure. No unexpected or severe adverse events were observed in any of the 3 dose cohorts. Table 1.1: Percent of subjects responding and average SFU/10 6 PBMC in responders for each antigen by cohort in Protocol HPV- 001 Interferon -γ ELISpot Cohort Low (0.6 mg) Mid (2 mg) High (6 mg) Antigen %RR AVG %RR AVG %RR AVG 16E6 33% 107 50% 243 50% 1341 16E7 17% 198 50% 104 67% 143 18E6 50% 359 50% 338 83% 664 18E7 33% 159 17% 179 50% 834 Any 67% 221 67% 210 83% 556 RR = Response Rate The IL -12 plasmid dose is based on previous experience in the HVTN 080 study, where 1 mg of IL-12 plasmid was co -administered with PENNVAX®-B followed by EP. HIV-specific CD4+ T cell responses were generated in 67.9% (19/28) of PENNVAX®-B + IL -12 recipients after two vaccinations, compared to 30.0% (3/10) with PENNVAX®-B alone. Co-administration with IL -12 resulted in CD4+ T cell responses in ~81% vs. 44% without IL-12 after three doses. Deliver y of PENNVAX®-B via EP increased the frequency of CD8+ T cell responses even more dramatically. CD8+ responses were detected in 33 % of PENNVAX®-B and 52% of PENNVAX®-B + IL -12 recipients after 3 vaccinations. S ix months after the third vaccination 43% of individuals were still 22 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol able to respond to HIV peptide pools. Overall, 71% of individuals vaccinated with PENNVAX®- B + IL-12 plasmid followed by EP developed either a CD4+ or CD8+ T-cell response after the second vaccination and 89% developed CD4+ or CD8+ T-cell responses after the thi rd vaccination . As noted above the addition of the IL -12 plasmid to the vaccine did not alter the safety profile. We do not anticipate any significant risks with the administration of this dose. 1.5.2 Risks/Benefit Assessment In acco rdance with the International Conference on Harmonisation (ICH), this study has been designed to minimize risk to study subjec ts. Potential risks of study products and administration from studies using similar plasmids with the identical DNA backbone are l isted in Table 1.2. The potential side effects of treatment with the investigational products may include discomfort related to the electroporation technique such as local edema, swelling, or pain. Systemic side effects with vac cines based on the identica l SynCon ® backbone have been demonstrated to be generally safe in more than 5 80 subjects (data as of May 15 , 2015) . The potential benefit of this study is to determine whether this immunotherapy will generate protective levels of antibodies and cytotoxic T- cells as treatment for those with HPV associated HNSCCa . Table 1.2: Summary of Reported Adverse Events from previous clinical trials a nd Potential Risks of DNA based immunotherapy delivered IM+EP with CELLECTRA® Common • Mild to moderate administration site pain, erythema, tenderness, swelling, induration • Malaise/fatigue, myalgia, or headache in the first few days following injection Less common • Injection site hematoma, bruising/ecchymosis, laceration, other transient lesions, or bleeding related to the injection procedure • Arthralgia or nausea Uncommon or rare • Severe administration site pain or tenderness • Rash following injection/EP • Vasovagal reaction/lightheadedness/dizziness related to the injection/EP procedure • Transient changes in clinical laboratory values Unknown frequency or theoretical potential risks • Severe localized administration site reaction, such as sterile abscess or secondary bacterial infection • Allergic reaction, including urticaria, angioedema, bronchospasm, or anaphylaxis • Muscle dam age at the administration site • Autoimmune disease • Electrical injury • Disruption of function of implanted electronic medical devices • Exacerbation of cardiac arrhythmia • Effects on the fetus and on pregnancy 2 Study Objectives 2.1 Primary Objectives 23 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol Evaluate saf ety of treatment with INO -3112. 2.2 Secondary Objectives 1.