Regarding the primary analysis, 20 subjects will provide 95% confidence that the true incidence of SAEs is <17% if 0 SAEs are observed. If more than one subject in a cohort discontinues early for reasons other than toxicity from the immunotherapy, consideration will be given for replacement. 7.2 Statistical Methods The primary analysis will estimate safety parameters . The incidence of SAEs and the incidence of injection site reactions will be estimated along w ith exact Clopper Pearson 95% confidence intervals. T oxicity experience will also be recorded and summarized . In secondary analyses, immune response parameters will be estimated. For continuous outcomes, the mean and 95% confidence interval will be calculated using a t -distribution approach, and for binary outcomes, the proportion and exact Clopper Pearson 95% confidence interval will be calculated . In exploratory analyses, we will also estimate the distributions of progression -free survival (PFS) and ove rall survival (OS) will be estimated, and any observed anti -tumor responses will be summarized . PFS and OS will be measured from the time of instillation of the initial dose of immunotherapy . Both The variables will be potentially censored by the end of the subject’s observation. These distributions will be summarized using Kaplan- Meier survival curves and estimate d median time to event of each type. Anti- tumor response category frequencies will be calculated. 7.3 Subject Population(s) for Analysis Any subject who receives at least one dose of treatment will be included in the safety analys es. For immunogenicity and survival/anti -tumor analyses, the main analyses will utilize subjects who received their assigned number of doses. 8 Safety and Adverse Events 8.1 Definitions 8.1.1 Unanticipated Problems Involving Risk to Subjects or Others Any incident, experience, or outcome that meets all of the following criteria: • Unexpected in nature, severity, or frequency (i.e. not described in study -related documents such as the I RB-approved protocol or consent form, the investigators brochure, etc) 44 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol • Related or possibly related to participation in the research (i.e. possibly related means there is a reasonable possibility that the incident experience, or outcome may have been caused by the procedures involved in the research) • Suggests that the research places subjects or others at greater risk of harm (including physical, psychological, economic, or social harm). 8.1.2 Adverse Event An adverse event (AE) is defined as any unfavorable and u nintended change in the structure, function, or chemistry of the body, or worsening of a pre -existing condition, temporally associated with the use of a product whether or not considered related to the use of the product. In this study, such changes will be monitored, classified, and summarized, as Clinical or Laboratory AEs. Medical condition/diseases present before starting the investigational drug will be considered adverse events only if they worsen after starting Study Treatment. An unexpected AE is one not identified in the Clinical Investigator’s Brochure (CIB) or otherwise not expected from the characteristics of the clinical material. AEs include the following: • Pre- or post -treatment complications that occur as a result of protocol mandated proce dure during or after the first screening visit (before the administration of study drug) • Any pre -existing condition that increases in severity, or changes in nature during or as a consequence of the study drug phase of a human clinical trial, will also b e considered an AE • Complications and termination of pregnancy; • All AEs that occur from the screening visit onwards and throughout the duration of the study, including the follow-up off study treatment period should be recorded as an AE AEs do not include the following: • Medical or surgical procedures other than the definitive surgical procedure for Cohort I (e.g., surgery, endoscopy, tooth extraction, transfusion) performed; the condition that leads to the procedure is an AE • Pre-existing diseases or conditions or laboratory abnormalities present or detected before the screening visits that do not worsen • Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for elective surgery, social and/or convenience admissions). • Overdose without clinical sequelae • Any medical condition or clinically significant laboratory abnormality with an onset date before the consent form is signed and not related to a protocol associated procedure is not an AE. It is considered to be pre -existing and should be documented on the medical history CRF • Uncomplicated pregnancy (documented on a pregnancy CRF) • An induced elective abortion to terminate a pregnancy without medical reason (documented on a pregnancy CRF) 8.1.3 Serious Adverse Event A serious adverse event (SAE) is any AE that meets one of the following conditions: • Death during the period of surveillance defined by the protocol; 45 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol • Is immediately life -threatening (e.g., subject was, in the view of the Investigator, at immediate risk of death f rom the event as it occurred). This does not include an AE that, had it occurred in a more serious form, might have caused death; • An event requiring inpatient hospitalization or prolongation of existing hospitalization during the period of protocol defined surveillance (including any overnight stay in the hospital, regardless of the length of stay, even if the hospitalization is only a precautionary measure to allow continued observation. However, hospitalization (including hospitalization for an elective p rocedure) for a pre -existing condition that has not worsened, does not constitute an SAE (see Section 8.1.12); • Results in congenital anomaly or birth defect; • Results in persistent or significant disability/incapacity or substantial disruption of the abilit y to conduct normal life functions; • Is an important medical event that may not result in death, be life threatening, or require hospitalization, but based upon appropriate medical judgment, may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed above. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse; development of malignancies. Clarification of Serious Adverse Events • Death is an outcome of an AE, and not an adverse event in itself • The subject may not have been on investigational medicinal product at the occurrence of the event. Dosing may have been given as treatment cycles or interrupted temporarily before the onset of the SAE, but may have contributed to the event • “Life -threatening” means that the subject was at immediate risk of death from the event as it occurred. This does not include an event that might have led to death if it had occurred with greater severity • Complications that occur during hospitalizations are AEs. If a complication prolongs the hospitalization, it is an SAE • Inpatient hospitalization means the subject has been formally admitted to a hospital for medical reasons, for any length of time. This may or may not be overnight. It does not include presentation and care within an emergency department The i nvestigator should attempt to establish a diagnosis of the event on the basis of signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be documented as the AE and/or SAE and not the individual signs/symptoms. Serious adverse events that are ongoing should be followed until resolution. The reporting period for SAEs is described in Section 8.3. 8.1.4 Adverse Event Reporting Period 0-3 days after each Study Treatment . Study subjects will be directly observed by study personnel for 3 0-45 minutes after administration of Study Treatment for immediate reactions. The occurrence and severity of any AE during this period or the lack of same will be recorded. After 46 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol that, subjects will be given an oral thermometer and a Participant Reminder Diary. They will be asked to take and record their body temperature daily at the same time and to note and characterize in their own words any local or systemic events they experience, during this 3 day period after each Study Treatment. Throughout the Stud y . In addition to the daily record of oral temperature, administration site reactions, and systemic complaints recorded for 3 days after Study Treatment or until resolution, subjects will be queried at each study visit regarding the occurrence of any SAE o r other AE that may have occurred since the last study visit. They will be reminded to contact study personnel and immediately report any such event that occurs during the course of the study. These events will be recorded on the CRFs. The investigator will grade laboratory AEs and clinical AEs (based on discussions with study participants) with respect to the following levels of severity as defined in the document “Common Terminology Criteria for Adverse Events (CTCAE)”, NCI version 4.03 issued by the US Department of Health and Human Services : • Mild (Grade 1) • Moderate (Grade 2) • Severe (Grade 3) • Potentially Life Threatening (Grade 4) • Deaths (Grade 5) Adverse events should be captured once on the CRF at the maximum severity reported. 8.1.5 Causal Relationship of C linical Material to Adverse Events A related AE is one judged to have a suspected relationship to the administration of the clinical material, ( INO-3112) and the investigational CELLECTRA ® device. An AE may also be assessed as not related to the investigational product. The Investigator is responsible for reporting adverse events and causality (judging the relationship between the administration of the clinical material and a subsequent AE) because the investigator is knowledgeable about the subject (e.g., medical history, concomitant medications), administers the investigational product, and monitors the subject’s response to the investigational product. The Investigator is aware of the subject’s clinical state and thus may be sensitive to distinctions betw een events due to the underlying disease process versus events that may be product related and may have observed the event. The Sponsor will assess the overall safety of the investigational product and determine whether to report expeditiously to the regul atory agencies. Investigators should use their knowledge of the Study Subject, the circumstances surrounding the event, and an evaluation of any potential alternative causes to determine whether or not an adverse event is considered to be related to the study drug, indicating "yes" or "no" accordingly. Causality should be assessed by the Investigator as “yes, related” or “no, unrelated” by the following criteria: • Yes – there is a reasonable possibility that administration of the Study Treatment contributed to the event; • No – there is no reasonable possibility that administration of the Study Treatment contributed to the event and there are more likely causes. The following guidance should also be taken into consideration: 47 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol • Temporal relationship of event onset to the initiation of study drug; • Course of the event, considering especially the effects of dose reduction, discontinuation of study drug, or reintroduction of study drug (where applicable); • Known association of the event with the study drug or with simil ar treatments; • Known association of the event with the disease under study; • Presence of risk factors in the Study Subject or use of concomitant medications known to increase the occurrence of the event; • Presence of non -treatment- related factors that are kn own to be associated with the occurrence of the event For Study Subject receiving combination therapy, causality may be assessed individually for each protocol- mandated therapy or for the combination. 8.1.6 Preexisting Condition A preexisting condition is one that is present at the time of signing of Informed consent. A preexisting condition should be recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during the study period. 8.1.7 General Physical Examination Findings At screening, any clinically significant abnormality should be recorded as a preexisting condition. At the end of the study, any new clinically significant findings/abnormalities that meet the definition of an adverse event must also be recorded and docum ented as an adverse event. 8.1.8 Post-study Reporting Requirements All AEs and SAEs including deaths, regardless of cause or relationship, must be reported for subjects on study (including any protocol-required post- treatment follow -up). Investigators are not obligated to actively seek AEs or SAEs beyond the follow up period for subjects. However, if the investigator learns of an AE or SAE that occurs after the completion of termination visit and the event is deemed by the investigator to be related to the study treatment (following the guidelines in Section 8.1.5), he/she should promptly document and report the event to Inovio Pharmaceuticals. 8.1.9 Abnormal Laboratory Values Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory abnorma lities (e.g., serum chemistry, CBC, coagulation, CPK) independent of the underlying medical condition that require medical or surgical intervention or lead to investigational medicinal product interruption or discontinuation must be recorded as an AE, as w ell as an SAE, if applicable. In addition, laboratory or other abnormal assessments (e.g., electrocardiogram, vital signs) that are associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the definition of an AE (or SAE) as described in Sections 8.1.2 and 8.1.3. If the laboratory abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., anemia) not the laboratory result (e.g., decreased hemoglobin). A clinical laboratory abnormality should be documented as an adverse event if any one of the following conditions is met: • Requires therapeutic intervention or diagnostic tests 48 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol • Leads to discontinuation of study treatment • Has accompanying or inducing symptoms or signs • Is judged by the investigator as clinically significant Grade is an essential element of these criteria. Each CTCAE grading term in the current version is a unique representation of a specific event used for medical documentation and scientific analysis and is a single MedDRA Lowest Level Term (LLT ). Investigators are asked to take the CTCAE grading criteria into account when assessing if a laboratory abnormality qualifies as a laboratory AE. Their clinical judgment ultimately determines whether the abnormality in question is “clinically significant (CS)” or “not clinically significant (NCS)” and the severity of the event. CTCAE grading can be used as a reference when making this determination. It is the responsibility of the Investigators to ensure all AEs are accurately reported and graded. 8.1.10 Hospitalization, Prolonged Hospitalization or Surgery Any adverse event that results in hospitalization or prolonged hospitalization should be documented and reported as a serious adverse event as detailed in 8.1.3. Any condition related to surgery should be documented as an adverse event if the condition meets the criteria for an adverse event. Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse event in the following circumstances: • Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a preexisting condition. Surgery should not be reported as an outcome of an adverse event if the purpose of the surgery was elective or diagnostic and the outcome was uneventful. • Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. • Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it is a worsening or increase in frequency of hospital admissions as judged by the clinical investigator. 8.2 Recording of Adverse Events At each contact with the subject, the investigator must seek information on adverse events by specific questioning and, as appropriate, by examination. Information on all adverse events should be recorded immediately in the source document, and also in the appropriate adverse event module of the case report form (CRF). All clearly related signs, symptoms, and abnormal diagnostic procedures results should be recorded in the source document, though should be grouped under one diagnosis. All adverse events occurring during the study period must be recorded. Adverse events will be measured and graded in accordance with the document entitled “Common Terminology Criteria for Adverse Events (CTCAE)”, NCI version 4.03 issued by the US Department of Health and Human Services on June 14, 2010. 49 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol All AEs, regardless of severity, seriousness, or presumed relationship to study treatment, must be recorded using medical terminology in source documents and on the CRF. Whenever possible, a diagnosis should be documented, in lieu of symptoms. The source document and the CRF must contain the investigator’s opinion concerning the relationship of the AE to study treatment. AEs should be described with the following attributes: • Duration (start and end dates) • Seriousness • Severity • Causality • Action(s) taken • Outcome 8.3 Reporting of Serious Adverse Events and Unanticipated Problems Investigators and the protocol sponsor must conf irm to the adverse event reporting timelines, formats and requirements of the various entities to which they are responsible, but at a minimum those events that must be reported are those that are: • related to investigational product(s) , • unexpected, and • serious or involve risks to subjects or others (see definitions, section 8.1). If the report is supplied as a narrative, the minimum necessary information to be provided at the time of the initial report includes: • Study identifier • Study Center • Subject number • A description of the ev ent • Date of onset • Current status • Whether study treatment was discontinued • The reason why the event is classified as serious • Investigator assessment of the grade and association between the event and study treatment 8.3.1 Events Requiring Expedited Reporting Events requiring expedited reporting (ERER) will be defined as treatment - or EP -related adverse events including any of the following: 1. Grade 3 or greater injection site pain, tenderness, erythema, and/or induration recorded ≥ 1 hour after study treatment (see Table 6.1) 2. Grade 3 or greater fever within 7 days of study treatment 3. Grade 3 or greater systemic symptoms within 7 days of study treatment 50 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol as defined in the “Common Terminology Criteria for Adverse Events (CTCAE)”, version 4.03 issued by the US Department of Health and Human Services on June 14, 2010. The wors t grade for that particular event is to be documented on the CRFs. Sites should inform Inovio of any ERER within 72 hours to discuss whether further dosing should continue for that participant. 8.3.2 Stopping Rules (Criteria for Pausing of Study) 8.3.2.1 If at any time during the study one third (1/3) or more subjects experience an ERER assessed as possibly, probably or definitely related to study treatment, further enrollment and study treatments will be on hold immediately until a thorough investigation has been conducted by the Medical Monitors of Inovio and Principal Investigator. 8.3.2.2 Any SAE, potentially life threatening AE or death assessed as possibly, probably or definitely related to study treatment, further enrollment and study treatments will be on hold immediately until a thorough investigation has been conducted by the Medical Monitors of Inovio and Principal Investigator and IRB (if applicable). 8.3.2.3 If three or more subjects in this study, experience the same grade 3 or 4 adverse event, assessed as possibly, probably or definitely related to study treatment, further enrollment and study treatments will be on hold immediately until a thorough investigation has been conducted by the Medical Monitors of Inovio and Principal Investigator. 8.3.2.4 In the event of any unexpected Grade 4 toxicities, assessed as possibly, probably or definitely related to study treatment, further enrollment and study treatments will be on hold immediately until a thorough investigation has been conducted by the Medical Monitors of Inovio and Principal Investigator and IRB (if applicable). 8.3.2.5 The study will be on hold for any report of Grade 3 anaphylaxis from immunotherapy/EP in two or more subje cts (as graded per “Common Terminology Criteria for Adverse Events (CTCAE)”, version 4.03 issued by the US Department of Health and Human Services on June 14, 2010). Occurrence in three or more subjects will lead to an immediate halt of enrollment and further immunotherapy until full discussion has been conducted by the Medical Monitors of Inovio and Principal Investigator, IRB (if applicable) and the FDA. 8.3.3 Investigator reporting: Inovio Pharmaceuticals, Inc. Any study- related unanticipated problem posing risk of harm to subjects or others, and any type of serious adverse event, must be reported to Inovio within 24 hours of the event. To report such events, the SAE worksheets or a MedWatch 3500a form must be completed by the investigator and faxed /emailed to Inovio within 24 hours. The investigator will keep a copy of this SAE form on file at the study site. Report serious adverse events by facsimile/email to: TELEPHONE: EMAIL: safety@inovio.com 51 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol If there is a need to directly contact the medical monitor, please contact: MEDICAL MONITOR : , MD or designee MAILING ADDRESS : TELEPHONE: office Inovio Pharmaceuticals, Inc. 660 W. Germantown Pike, Suite 110 Plymouth Meeting, PA 19462 Mobile FACSIMILE (FAX): EMAIL: As soon as available, the investigator must provide further information on the serious adverse event or the unanticipated problem in the form of a written narrative. This should include an updated MedWatch Form, and any other diagnostic information that will assist the understanding of the event. Significant new information on ongoing serious adverse events should be provided promptly to Inovio. Inovio will be responsible for reporting any applicable events to the U.S. Food and Drug Administration (FDA) per their reporting requirements. 8.3.4 Investigator Reporting: the Penn IRB The University of Pennsylvania IRB (Penn IRB) requires expedited reporting of those events related t o study participation that are unforeseen and indicate that participants or others are at increased risk of harm. The Penn IRB will not acknowledge safety reports or bulk adverse event submissions that do not meet the criteria outlined below. The Penn IR B requires researchers to submit reports of the following problems within 10 working days from the time the investigator becomes aware of the event: • Any adverse event (regardless of whether the event is serious or non- serious, on- site or off- site) that occ urs any time during or after the research study, which in the opinion of the principal investigator is: Unexpected (An event is “unexpected” when its specificity and severity are not accurately reflected in the protocol -related documents, such as the IRB -approved research protocol, any applicable investigator brochure, and the current IRB -approved informed consent document and other relevant sources of information, such as product labeling and package inserts.) AND Related to the research procedures (An event is “related to the research procedures” if in the opinion of the principal investigator or sponsor, the event was more likely than not to be caused by the research procedures.) Deaths occurring for subjects on-study and within 30 days of study drug admi nistration that are considered unforeseen and indicates participants or others are at increased risk of harm (i.e. unexpected and probably/definitely related), must be reported to the IRB within 24 hours of notification. Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical Investigator’s study file. 52 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol 8.3.5 Other Reportable Events: For clinical drug trials, the following events are also reportable to the Penn IRB: • Any adverse experience that, even without detailed analysis, represents a serious unexpected adverse event that is rare in the absence of drug exposure (such as agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome). • Any adverse event that would cause the sponsor to modify the investigators brochure, protocol or informed consent form, or would prompt other action by the IRB to assure protection of human subjects. • Information that indicates a change to the risks or potential benefits of the research, in terms of severity or frequency. For example: – An int erim analysis indicates that participants have a lower rate of response to treatment than initially expected. – Safety monitoring indicates that a particular side effect is more severe, or more frequent than initially expected. – A paper is published from anot her study that shows that an arm of your research study is of no therapeutic value. • Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic used in a research protocol. • Breach of confidentiality • Change to the protocol take n without prior IRB review to eliminate apparent immediate hazard to a research participant. • Incarceration of a participant when the research was not previously approved under Subpart C and the investigator believes it is in the best interest of the subject to remain on the study. • Complaint of a participant when the complaint indicates unexpected risks or the complaint cannot be resolved by the research team. • Protocol violation (meaning an accidental or unintentional deviation from the IRB approved protocol) that in the opinion of the investigator placed one or more participants at increased risk, or affects the rights or welfare of subjects. The IRB will accept other reports when the investigator is unsure whether the event should be reported, and the IRB w ill review such reports to determine whether the event meets the threshold for an unanticipated event presenting risk to the participant. , Institutional Review Board Phone: Fax: 8.4 Reportable Events Deviation A one -time unintentional action or process that departs from the IRB approved study protocol, involving one incident and identified retrospectively , after the event occurred. If the impact on the protocol disrupts the study design, may affect the outcome (endpoints) or compromises the 53 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol safety and welfare or the subjects, the deviation must be reported to the Sponsor (Inovio) as soon as possible. 8.5 Reporting of Device Related Complaints Any pro blems experienced during the treatment procedure including potential malfunctions of the CELLECTRA® device, error messages displayed on the device screen following treatment or errors that occur during the treatment procedure should be reported to the Sponsor or designee immediately for evaluation via email to . The Error Reporting Form provided will be completed and sent to Inovio or its designee. 9 Data Handling and Record Keeping 9.1 Confidentiality Information about study subjects will be kept confidential and managed according to the requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require a signed subject authorization informing the subject of the following: • What protected health i nformation (PHI) will be collected from subjects in this study • Who will have access to that information and why • Who will use or disclose that information • The rights of a research subject to revoke their authorization for use of their PHI. In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the ability to use all information collected prior to the revocation of subject authorization. For subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 9.2 Source Documents Source data is all information, original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents. Examples of these original documents, and data records include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at medico -technical departments involved in the clinical trial. 9.3 Case Report Forms The study case report form (CRF) is the primary data collection instrument for the study. All data requested on the CRF must be recorded. All missing data must be explained. If a space on the CRF is left blank because the procedure was not done or the question was not asked, write “N/D”. If the item is not applicable to the individual case, write “N/A”. 9.4 Records Retention It is the investigator’s responsibility to retain study essential documents for at least 2 years after the last approval of a marketing application in their country and until there are no pending or 54 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol contemplated marketing applications in their country or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period if required by an agreement with the drug manufacturer . In such an instance, it is the responsibility of the drug manufacturer to inform the investigator/institution as to when these documents no longer need to be retained. 10 Study Monitoring, Auditing, and Inspecting 10.1 Study Monitoring Monitoring of the clinical trial will be performed by experienced monitors, who will report to the Sponsor or the Sponsor designee. Records for all clinical subjects in this trial will be monitored. The following clinical site monitoring tasks will be performed at all sites: • Prior to trial initiation, a site visit will be conducted to review all relevant forms and documentation, to ensure compliance with all applicable requirements • All clinical site monitoring visits will be d ocumented • Periodic site visits will be performed throughout the study • The site monitor will be responsible for addressing and documenting the following study conduct activities and obligations and will: ○ Assure that the study is being conducted in accordance with the protocol, applicable regulatory agency regulations, and IRB/EC policies ○ Discuss study conduct issues and incidents of noncompliance with the Investigator and/or study personnel and document them on the resolution trip report. Report any signific ant unresolved problems immediately to the sponsor ○ Remind the Investigator as necessary of the obligation to immediately report all serious adverse events (SAE) and provide subsequent follow -up report of the final outcome to the IRB/EC ○ Inspect all Case Rep ort Form (CRF) pages for completeness, logic, and internal consistency throughout the study ○ Assure that the study facilities continue to be acceptable ○ Compare the study CRFs with source documents to assure that the data are accurate and complete and that t he protocol is being followed ○ Assure that test article accountability and reconciliation records are complete and accurate ○ Assure that all subject specimens are being stored and forwarded properly for testing 10.2 Medical Monitor The medical monitor for this study will be Dr. from Inovio Pharmaceuticals or a designee. 10.3 Auditing and Inspecting The investigator will permit study -related monitoring, audits, and inspections by the EC/IRB, the IND S ponsor or its designee , government regulatory bodies, and University compliance and quality assurance groups of all study related documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.). The investigator will ensure the capability for inspections of applicable study -related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 55 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol Participation as an investigator in this study implies acceptance of potential inspection by government regulatory authorities and applicable University compliance and quality assurance offic es. 11 Ethical Considerations 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 Instituti onal research policies and procedures. This protocol and any amendments will be submitted to a properly constituted independent Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the study conduct. The decision of the IRB concerning the conduct of the study will be made in writing to the investigator and a copy of this decision will be provided to Inovio Pharmaceuticals before commencement of this study. All subjects for this study will be provided a consent form describing this study and providing sufficient information for subjects to make an informed decision about their participation in this study. This consent form will be submitted with the protocol for review and approval by the IRB and CTSRMC for the study. The formal consent of a subject, using the IRB -approved consent form, must be obtained before that subject undergoes any study procedure. The consent form must be signed by the subject and the investigator -designated research professional obtai ning the consent. 12 Study Finances 12.1 Funding Source The study will be supported by funds through the Abramson Cancer Center’s EARLY PHASE CLINICAL RESEARCH SUPPORT . Funding for immunological correlatives and vaccine will be provided by Inovio Pharmaceuticals, Inc. We will not be receiving additional funding through Inovio. 12.2 Conflict of Interest Investigators on this protocol do not have a conflict of interest with this study (patent ownership, royalties, or financial gain greater than the minimum allowable by their institution, etc.) All University of Pennsylvania investigators will follow the University conflict of interest policy. 13 Publication Plan Publication policy shall be as provided in Section 4.3 of the Clinical Trial Agreement between the University of Pennsylvania and Inovio Pharmaceuticals, Inc. 56 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol 14 List of Abbreviations AE Adverse Event ALT (SGPT) Alanine Aminotransferase (Serum Glutamic Pyruvic Transaminase) ANC Absolute Neutrophil Count AST (SGOT) Aspartate Aminotransferase (Serum Glutamic Oxaloacetic Transaminase) CBC Complete Blood Count Chemo XRT Chemoradiation Therapy CIN Cervical Intraepithelial Neoplasia CMI Cell Mediated Immunity CPK Creatine Phosphokinase CRF Case Report Form CTCAE Common Terminology Criteria for Adverse Events DNA Deoxyribonucleic Acid ECG Electrocardiogram ECOG Easter Cooperative Oncology Group EP Electroporation FDA Food and Drug Administration HBsAg Hepatitis B Surface Antigen HNSCCa Head and Neck Squamous Cell Carcinoma HCG Human Chorionic Gonadotropin HIV Human Immunodeficiency Virus HPV Human Papillomavirus ICH International Conference on Harmonisation IEC Independent Ethics Committee IRB Institutional Review Board ISH In Situ Hybridization IUD Intrauterine Device IM Intramus cular IP Investigational Product LFT Liver Function Test PBMC Peripheral Blood Mononuclear Cells PCR Polymerase Chain Reaction 57 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol RBC Red Blood Cells SAE Serious Adverse Event SFU Spot Forming Units SOC System Organ Class TILs Tumor Infiltra ting Lymphocytes ULN Upper Limit of Normal WBC White Blood Cells 58 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol 15 References 1. Siegel R, Naishadham D, Jemal A.