Any other conditions judged by the investigator that would limit the evaluation of a subject. 12 Date: 8 April, 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol Table S1: Cohort I Schedule of Events Pre-surgery (Up to 2 doses of immunotherapy 3 weeks apart ± 3 days ) Post-surgery (Up to 3 doses of immunotherapy, 3 weeks apart; ± 3 days ). Subjects will receive no more than 4 doses of Immunotherapy (to include both pre and post -surgery dosing). Screening1 Pre Dose Post Dose Surgery 2 wk Post surgery Inspection Visit2 2 wk f/u post last dose LTFU / EOS3 Procedures Informed Consent X Medical History X Physical Exam4/Assessment X X X X X X Performance Status (ECOG) X X X X X X Concomitant Medications X X X X X X Adverse Events X X X X X X X Injection site assessment X5 X Wound healing Inspection X Tumor evaluation X Clinical Labs CBC w diff (4ml) X X6 X X Chemistry (5ml)7 X X6 X X PT-INR/PTT (4ml) X B-hCG (1ml)8 X X Viral Serology (5ml)9 X CPK (1ml) X X Other Clinical Procedures ECG 12 -lead X Research Immunology Serum and Whole Blood (1 Red Top and 4 ACD tube)10 X X X X X X X Tissue Sample11 X X HLA Testing (no action required) X12 IMMUNOTHERAPY X Download EP Data X Patient Reminder Card X 1- Screening to be done within 28 days prior to first dose. If a subject is rescreened, the screening clinical labs and 12 - lead ECG must be repeated unless they will occur within 4 weeks of the subject’s first dose. All other screening procedures do not need to be repeated. 2- Inspection visit occurs 4 weeks post -surgery (± 7 days) 3- LTFU: Long term follow up: every 3 months ( ±7 days) for 6 months from the last dose of immunotherapy , End of Study (EOS) defined as last LTFU visit 4- Includes weight, vital signs, oxygen saturation (height will be collected as part of Screening visit). Assessment includes 13 Date: 4 April , 2-16 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol medical/clinical assessment 5- To be done 30 -45 minutes post dose 6- If clinic al screening labs (CBC and Chemistry) were performed within 72 hours prior the subject’s first dose , these labs are not required to be redrawn prior to the subject’s first dose 7- Total serum bilirubin, alkaline phosphatase, AST (SGOT), ALT (SGPT), serum creatinine, serum electrolytes, serum calcium, serum albumin. 8- Women of childbearing potential. Serum β-hCG at screening and Urine β-hCG within 72 hours of each dose. 9- Antibody to human immunodeficiency virus (HIV- Ab), Hepatitis B surface antigen (HBsA g), antibody to Hepatitis C virus (HCV) 10- At least 34 mL (4 x 8.5 mL ACD tubes) whole blood and 4 mL serum per time point to be collected. A total of at least 68 mL whole blood and 4 mL serum should be collected prior dosing on Day 0. 11- P araffin -embedd ed tumor tissue or unstained slides for IHC and ISH . Fresh cut primary tumor tissue at the time of surgery. 12- To be performed using available PBMC from whole blood immunology sample. 14 Date: 4 April , 2-16 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol Table S2: Cohort II Schedule of Events Immunotherapy starts ~2 -6 mo nths post chemoradiation. Doses are q3 weeks ( ± 3 days) . Screening1 Pre Dose Post Dose 2 wk f/u post last dose LTFU /EOS2 Procedures Informed Consent X Medical History X Physical Exam3/Assessment X X X X Performance Status (ECOG) X X X X Concomitant Medications X X X X Adverse Events X X X X X Injection site assessment X4 Clinical Labs CBC w diff (4ml) X X5 X X Chemistry (5ml)6 X X5 X X PT-INR/PTT (4ml) X B-hCG (1ml)7 X X Viral Serology (5ml)8 X CPK (1ml) X X Other Clinical Procedures ECG 12 -lead X Research Immunology Serum and Whole Blood (1 Red Top and 4 ACD tube)9 X X X X Tissue Sample10 X HLA Testing (no action required) X11 IMMUNOTHERAPY X Download EP Data X Patient Reminder Card X 1- Screening to be done within 28 days prior to first dose. If a subject is rescreened, the screening clinical labs and 12 -lead ECG must be repeated unless they occur within 4 weeks of the subject’s first dose. All other screening procedures do not need to be repeated. 2- LTFU: Long term follow up: every 3 months (± 7 days) for 6 months from the last dose of immunotherapy, End of Study (EOS) defined as last LTFU visit 3- Includes weight, vital signs, oxygen saturation 4- To be done 30-45 minutes post dose 5- If clinical screening labs (CBC and Chemistry) were performed within 72 hours prior the subject’s first vaccination, these labs are not required to be redrawn prior to the subject’s first dose 6- Total serum bilirubin, alkaline phosphatase, AST (SGOT), ALT (SGPT), serum creatinine, serum electrolytes, serum calcium, serum albumin. 7- Women of childbearing potential only. Serum β-hCG at screening and Urine β-hCG within 72 hours of each dose 15 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol 8- HIV, Hepatitis BsAg, Hepatitis C 9- At least 34 mL (4 x 8.5 mL tubes) whole blood and 4 mL serum per time point to be collected. A total of at least 68 mL whole blood and 4 mL serum should be collected prior to dosing on Day 0. 10- Paraffin -embedded tumor tissue or unstained slides for IHC and ISH. C onfirmati on of HPV-16 and/or HPV-18 positivity prior to first dose . 11- To be performed using available PBMC from whole blood immunology sample. 16 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol 1 Introduction This document is a protocol for a human research study. This study is to be conducted according to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), applicable government regulations and Institutional research policies and procedures. 1.1 Background 1.1.1 HPV related squamous cell ca rcinoma of the head and neck Squamous cell carcinoma of the head and neck (HNSCC) is diagnosed in over 500,000 patients worldwide each year, accounting for 5% of all malignancies [1]. A significant subset of HNSCCa is now known to be caused by oncogenic human papilloma virus (HPV) infection. HPV - associated SCCa arises predominantly in the oropharynx and occurs in patients (strong male predominance) without a strong tobacco and/or alcohol consumption history. In a retrospective study, tumor tissues from 253 patients with newly diagnosed or recurrent HNSCCa were tested for the presence of HPV genome by use of polymerase chain reaction (PCR) -based assays, Southern blot hybridization, and in situ hybridization (ISH). The viral E6 coding region was sequenced to confirm the presence of tumor -specific viral isolates. HPV was detected in 62 (25%) of 253 cases. High risk, tumorigenic type HPV16 was identified in 90% of the H PV-positive tumors. HPV -16 was localized specifically by ISH within the nuclei of cancer cells in pre- invasive, invasive, and lymph node disease. Southern blot hybridization patterns were consistent with viral integration. Poor tumor grade and oropharyngeal site independently increased the probability of HPV presence [ 2]. The molecular and clinical profiles of HPV positive tumors are distinct from those of HPV negative cancers. In the typical HPV negative squamous cell carcinomas, p53 mutations are frequent along with decreased p16 and increased levels of pRb [3]. By contrast, HPV positive carcinomas are associated with wild type (albeit dysregulated) p53, down regulation of pRb, and up-regulation of p16, the latter serving as a surrogate marker for the disease itself. As compared with HPV- negative oropharyngeal cancer s, HPV positive oropharyngeal cancers are less likely to occur among moderate to heavy drinkers and smokers, have characteristic basaloid morphology, and have improved disease- specific survival [2]. The HPV viral oncoproteins, E6 and E7, are predominantly responsible for oncogenesis. Like many viral oncoproteins, E6 and E7 are expressed early in the course of infection and have multifunctional roles. E6 promotes degradation of p53, indirectly activates telomerase, and disrupts the function of the cellular phosphatase tumor suppressor PTPN13. E7 inactivates pRb and activates Mi2beta. Together, these oncogenic alterations drive rapid cellular proliferation, suppress or downregulate key tumor suppressor proteins, and lead to cellular immortality. In addition, E6/E7 expression is vital for malignancy and is required to maintain a malignant transformed phenotype [4]. It has been shown that persistence of malignant cells requires the continuous expression of the human papillomavirus type 16 oncoge nes [5]. Tumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer. HPV related tumors are generally more responsive to chemotherapy and radiation compared to non- HPV related HNSCCa [ 6]. In a landmark retrospective analysis of RTOG0129, Ang et al. described that patients with HPV related tumors had superior 3- year rates of overall survival compared to non- HPV related tumors. After adjusting for age, race, tumor and 17 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol nodal stage, tobacco exposure, and treatment assignment, patient with HPV -related HNSCCa had a 58% reduction in the risk of death (hazard ratio, 0.42; 95% CI, 0.27 to 0.66). Smoking history had a significant impact on survival in this otherwise favorable prognosis population; the risk of death increased significantly with each additional pack- year of tobacco smoking [ 6]. Despite the availability of highly curative treatments, at least 10 -30% of patients with HPV related HNSCCa (depending on smoking status and other unknown variables) will eventually develop locally recurrent and/or metastatic disease. The prognosis of patients with locally recurrent or metastatic HNSCCa is dismal, and palliative treatment options remain extremely limited. A few patients with recurrent disease are candidates for salvage therapies, including potentially curative surgery [7]. Highly selected patients in this setting may benefit from re - irradiation although the morbidity of this approach is substantial [8]. Palliative systemic therapy remains the mainstay for most patients. Despite the availability of cytotoxic chemotherapy and targeted agents like cetuximab , median survival for patients with incurable HNSCCa is around 10.5 months [ 9]. 1.1.2 Rationale for HPV specific immunotherapy with a therapeutic HPV vaccine Current treatment of HPV related HNSCC could potentially be improved with addition of immunotherapy. Commercially available preventive HPV vaccines generate neutralizing antibodies against HPV major capsid protein L1, but they do not exert therapeutic effects on existing lesions and are unlikely to have an effect on HPV associated malignancy because they do not engender a cytolytic T -cell response [10]. HPV specific immunotherapy, on the other hand, may eliminate preexisting lesions and infections by generating cellular immunity against HPV infected cells. HPV E6 and E7 oncoproteins rep resent ideal targets for therapeutic intervention because of their constitutive expression in HPV associated tumors and their crucial role in the induction and maintenance of HPV associated disease [10]. One therapeutic approach is to modify the virus itself and use it as an immunogen. In a recent study, Wieking et al. described the generation of a mutant non -oncogenic HPV16 E6D/E7D construct. This construct, expres sed either as a stable integrant or in the [E1 -, E2b- ] adenovirus, lacks the ability to transform human cells but retains the ability to induce an HPV -specific immune response. In a mouse model, vaccination with Ad5 [E1- , E2b -]-E6D/E7D in immune competent mice enhanced immune related clearance in vivo during standard therapy for HPV related cancer with cisplatin and radiation [11]. 1.1.3 Rationale for immunotherapy wi th synthetic DNA delivered by electroporation The delivery of synthetic DNA using electroporation represents another approach that offers several potential advantages. Synthetic DNA in the form of a plasmid are not known to elicit anti - vector immune responses, providing the capacity for repeated administrations that may be required to achieve and maintain effective immune responses. Furthermore, the plasmids can be engineered to express a variety of HPV related antigenic peptides and/or proteins [ 10]. Inovio has developed a novel immunotherapeutic from synthetic HPV -16/18 E6 and E7 DNA sequences. Phase 1 clinical results with VGX -3100 delivered by in vivo electroporat ion (EP) were recently published [12]. Eighteen women previously treated for cervical intraepithelial neoplasia (CIN) grade 2 or 3 were treated with a three-dose (intramuscular) regimen of a highly engineered DNA (VGX -3100) in a dose escalation study (0.3, 1, and 3 mg per plasmid). HPV specific CD8+ T cells were shown to exhibit full cytolytic functionality in all cohorts. VGX -3100 was shown to drive robust immune responses to E6 and E7 from high- risk HPV serotypes and could thereby 18 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol contribute to elimination of HPV infected cells and subsequent regression of the HPV induced dysplastic process [12]. Because E6 and E7 are responsible for the transformation of cancer cells and are required for maintenance of HPV associated HNSCC, we hypothesize that generation of robust T -cell immunity to E6 or E7 will lead to down- regulation of cancer survival pathways and disease stabilization or regression. 1.1.4 Rationale for addition of IL -12 p lasmid DNA molecular adjuvant DNA vaccines primarily elicit CD4+ T-cell responses in humans, and there has been interest in discovering ways to boost the immune response post vaccination. In addition to electroporation, Inovio has also shown that IL -12 DNA can be used as a molecular adjuvant to enhance immune responses. This is done by co- delivering DNA plasmids expressing immune modulators. The IL - 12 DNA adjuvant is a dual promoter expression plasmid expressing the genes encoding human IL-12 proteins p35 and p40 under separate regulatory control. In a clinical study with a similarly designed HIV DNA immunogen, co -administration of IL -12 DNA with DNA encoding antigenic proteins was associated with an enhanced CD8 vaccine immune response [13, 14]. The use of IL-12 DNA was associated with expansi on of antigen- specific IFN -γ positive effector cells as well as granzyme B production. The immunity induced included both a CD8 as well a CD4 component [15, 16]. The evaluation of recombinant IL -12 DNA has yielded a wealth of safety information to date in humans and forms the preliminary basis for the predicted safety profile for the use of IL -12 plasmid as an adjuvant component of the vaccine in the proposed clinical study. 1.1.5 Rationale for e lectroporation (EP) with CELLECTRA ® device The use of EP with the CELLECTRA device has been shown to increase the expression of VGX- 3100. EP is the use of transmembrane electric field pulse to induce microscopic pathways (pores) in a bio- membrane. The electric field allows macromolecules, ions, and water to pass from one side of the membrane to the other. The presence of a constant field influences the kinetics of directional translocation of the macromolecular plasmid, such that the plasmid delivery in vivo has been sufficient to achieve physiological levels of secreted proteins. Intramuscular injection of plasmid followed by EP has been used very successfully to deliver ther apeutic genes that encode for a variety of hormones, cytokines or enzymes in a variety of species [17]. The design of software that enables constant current EP to deliver plasmids allows for the individual resistance of the treated muscle to be taken into consideration and yields highly efficient in vivo plasmid expression [ 18]. Ten healthy adults were electroporated using CELLECTRA , to evaluate the pain following EP in 10 healthy subjects, was evaluated immediately after, and at 5, 15, 30 minutes and 1 hour after the procedure. Subjects used a Visual Analog Scale (VAS) questionnaire, 10 cm in length, anchored by word descriptors at each end, “No Pain” and “Worst Pain”, to mark their pain related to the treatment. Subjects reported a mean (±sem) score of 6.3 (±0.7) immediately after treatment and 2.8 (±0.5) approximately 5 minutes after the procedure [19]. These data show that the pain associated with electroporation is acute and diminishes quickly. Therefore, the risk to subjects is minimal, and benefit outweighs the risk. 19 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol In this proof of concept study , we propose to evaluate the safety and immune effects of the immunotherapy with VGX -3100, synthetic plasmid DNA encoding HPV -16 and HPV -18 E6/E7 antigens co -administered with a recombinan t IL-12 molecular adjuvant ( INO-9012). 1.2 Investigational Agents 1.2.1 VGX -3100 (Common Name) Chemical Name : Circular, double stranded, deoxyribonucleic acid consisting of 3782 base pairs for the pGX3001 plasmid and 3824 base pairs for the pGX3002 plasmid. Disting uishing Name : Eukaryotic expression plasmids containing HPV -16 and -18 E6 & E7 - encoding transcription unit controlled by a synthetic, CMV promoter, and elements required for replication and selection in E. coli , namely a pUC origin of replication (pUC Ori) and a kanamycin resistance gene (Kan R). 1.2.2 INO -9012 (Common Name) Chemical Name : Circular, double stranded, deoxyribonucleic acid consisting of 6259 base pairs for the pGX6001 (also called IL-12 DNA) plasmid. Distinguishing Name : Eukaryotic expression plasm ids containing synthetic IL -12 p35 light chain and p40 heavy chain (pGX6001) controlled by a dual promoter vector, a bGH poly A tract, bacterial origin of replication to support production of the plasmid in E. coli , and a kanamycin resistance gene (Kan R). VGX-3100 and INO-9012 combination is referred to as INO-3112 in this protocol. 1.2.3 CELLECTRA®5P device for intramuscular electroporation The CELLECTRA®5P device is a portable, battery powered medical device designed to generate a minimally controlled electric field which temporarily and reversibly increases cellular membrane permeability without damaging the tissue. During the period of increased permeability, an injected plasmid DNA formulation can be injected into the cells.