Subjects will be required to give written consent of study participation before any screening tests or evaluations are conducted. 4.4 Early Withdrawal of Subjects 4.4.1 When and How to Withdraw Subject s Subjects who do not complete the study protocol will be considered to have prematurely discontinued the study. The reasons for premature discontinuation (for example, voluntary withdrawal, toxicity, death) must be recorded on the case report form (CRF). Final study evaluations will be completed at the time of discontinuation if it is possible . Reasons for withdrawal include, but are not limited to the following: 1. Inter -current illness that would, in the judgment of the investigator, affect assessments of clinical status to a significant degree or r equire discontinuation of study; 2. Unacceptable toxicity: Subjects will be followed until resolution or stabilization; 3. Disease progression; 4. Subject withdraws consent; 5. Treatment delay greater than four weeks for any toxicity; 6. Subjects who do not have satisfactory compliance with study procedures; 7. Major protocol violations, including, but not limited to: a. failure to meet major inclusion/exclusion criteria; b. failure to complete full evaluations as required by protocol; c. use of concomitant therapies. If any subject in a cohort discontinues early for reasons other than toxicity from immunotherapy, consideration will be given for replacement . If a subject discontinues Study Treatments before completion of long term follow up for 6 months post the last dose of immunotherapy, all assessments for the end of Study Treatment visit and/or end of study visit should be performed. Subjects who have disease progression confirmed and/or start new anti- cancer therapy will be discontinued from the study. In both Cohorts, subjects who progress in their disease, once confirmed, will be required to come for the end of the study visit. All subjects will be followed for survival status regardless of the cause of death. In the case of a fatal out come, all relevant information (including cause of death, autopsy report, ER/hospital record, concomitant medication, and relationship to Study Treatment or underlying disease) will be collected. 4.4.2 Data Collection and Follow- up for Withdrawn Subjects Subjec ts taken off study due to treatment related toxicity will be followed until resolution or stabilization. All subjects will be followed for survival status regardless of the cause of death . 30 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol 5 Study Drug 5.1 Description Investigational product is defined as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in the study. VGX-3100, the active investigational product to be used in this study, is a mixture of two separate DNA plasmids encoding E6 and E7 proteins of HPV types 16 and 18 . INO -9012 is a DNA plasmid expressing the p35 and p40 human IL -12 subunits off of separate promoters within the same plasmid. VGX -3100 and INO-9012 combination is referenced as INO -3112. INO-3112 (6 mg VGX -3100 + 1 mg INO -9012) is delivered by IM with EP for subjects in Cohort I and Cohort II. INO-3112 will be provided by Inovio Pharmaceuticals, Inc. or its designee. Table 5.1 Investigational Products Product Concentration Dosage Form & Route of Administration Dosea (mL) VGX- 3100 6 mg/mL* Sterile water for injection with 1% poly -L- glutamate sodium salt via IM injection 1.1# INO- 9012 10 mg/mL* Sterile water for injection via IM injection *Target concentration of the DNA plasmid. The actual concentration may vary slightly in the lot used for this study. aVGX- 3100 and INO -9012 combined to deliver 1.1 m L (Cohorts I and II). # There is no exception on dosing change in immunotherapy for any cohort 5.2 Packaging VGX-3100 and INO-9012 vials will be shipped directly from the manufacturer or its designee to each individual study site or regional depot. Each vial will be labeled with a single panel label. Vials will only be handled by designated personnel (e.g. pharmacist) at each site. When a subject is eligible for enrollment, personnel will combine the appr opriate investigational products as detailed in section 5.3.5 (Preparation of Investigational Product) then provide to the clinical personnel. Sample vial text for each investigational product is provided below: VGX- 3100 SynCon™ VGX -3100 [6mg/mL] 1 mL/via l Lot: VGX -3100. xxxxxx Date of Manufacture: DD MMM YY Final Retest Date: DD MMM YY Store frozen at or below -15C CAUTION: New Drug – Limited by Federal Law to Clinical Trial Use Only Inovio Pharmaceuticals Inc 660 W Germantown Pike , Plymouth Meeting, PA 1946 2 USA 31 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol INO- 9012 SynCon™ INO -9012 [10 mg/mL] 0.2 mL/vial Single Use Vial Lot: INO -9012.xxxxxx Date of Manufacture: DD MMM YY Final Retest Date: DD MMM YY Store frozen at or below -15°C CAUTION: New Drug – Limited by Federal Law to Investigational U se. Inovio Pharmaceuticals Inc. Rev 000 5.3 Receiving, Storage, Dispensing and Return 5.3.1 Receipt of Drug Supplies Inovio Pharmaceuticals, Inc. will be responsible for assuring the quality of the investigational product is adequate for the duration of the trial. Unless otherwise specified, the product will be shipped frozen on dry ice. If there is no dry ice remaining in the shipment container when the shipment is received Inovio, or its designee should be contacted immediately. 5.3.2 Storage Investigational product(s) should be stored in a secure area according to local regulations. The product should be transferred from the shipping container to the appropriate storage conditions (frozen at -15ºC or below) upon arrival. Freezer and refrigerator temperature logs must be maintained at the clinical site and temperatures must be recorded and monitored regularly. The principal i nvestigator and study team will ensure that a current record of investigational product disposition is maintained at the study site where investigational product is inventoried and disposed. Records or logs must comply with applicable regulations and guidelines, and should include: • Amount received and placed in storage area; • Amount currently in storage area; • Label ID number or batch number and use date or expiry date; • Dates and initials of person responsible for each investigational product inventory entry/movement; • Amount dispensed to each subject, including unique subject identifiers; • Amount transferred to another area/site for dispensing or stor age; • Amount returned to Sponsor; • Amount destroyed at study site, if applicable. 5.3.3 Dispensing of Study Drug It is the responsibility of the Investigator to ensure that product is only dispensed to study participants. It must be dispensed only from official study sites by authorized personnel according to local regulations. The site will identify a dedicated investigational pharmacist to dispense IP. Their duties will include the receipt, storage, preparation and maintenance of records for the IP. 32 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol The VGX-3100 and INO-9012 vials should be removed from the freezer and thawed at room temperature to ensure complete thaw . The thawed product must be used within 4 hours of removal from freezer. All material removed from the freezer must not be re -frozen. 5.3.4 Precautions with Investigational Medicinal Product A dose of the study product known or suspected to have been taken (accidentally or intentionally) exceeding the dose mandated by the protocol, and any misuse or abuse of study products or any other product taken as a concomitant medication, whether or not associated with an adverse experience, must be reported to Inovio Pharmaceuticals within 24 hours. Any clinical sequelae in association with the overdose should be reported as an AE or SAE. Details of signs or symptom s, clinical management , and outcome should be reported, if available. 5.3.5 Preparation of Investigational Product Prior to administering to subjects the investigational products will be combined by authorized personnel into a single syringe using the following procedure: Required Materials: (1) or (2) vials SynConTM VGX-3100, thawed (1) vial SynConTM INO-9012, thawed (1) 2 mL sterile empty vial (1) 0.5 mL or 1.0 mL syringes (2) 3 mL syringes (1) 21 gauge, 2” needle (2) 21 gauge, 1.5” needles Note: T he second vial of SynCon TM VGX -3100 should only be thawed if less than 1.1 mL is withdrawn from the first vial in Step ( 1) below: 1. Using aseptic technique, withdraw the entire contents from the vial SynConTM VGX- 3100 with a 3 mL syringe and a 2” 21 gauge needle; a ne edle of a minimum length of 2” is recommended to be able to withdraw the entire contents of the larger vial. 2. If the volume of VGX -3100 in the syringe is less than 1.1 mL , perform Formulation Instruction Set A. 3. If the volume of VGX -3100 in the syringe is exactly 1.1 mL , perform Formulation Instruction Set B. 4. If the volume of VGX -3100 in the syringe is 1.2 mL or more , perform Formulation Instruction Set C. Formulation Instruction Set A (less than 1.1 mL VGX-3100 withdrawn): 1. Thaw a second vial of SynConTM VGX-3100. 2. Once the vial is thawed, using the same syringe/needle from the first vial, withdraw a sufficient volume of VGX -3100 from the second vial to total at least 1.2 mL of VGX - 3100 in the syringe. 3. Inject 1.2 mL of VGX- 3100 into an empty sterile vial; set this “mixing” vial which now contains 1.2 mL of VGX -3100 aside. 33 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol 4. Using a new 0.5 or 1.0 mL syringe with a 1.5” 21 gauge needle, withdraw 0.12 mL from the vial SynConTM INO-9012 and add the 0.12 mL to the “mixing” vial containing 1.2 mL of VGX- 3100. The final volume of this vial should now be approximately 1.32 mL of VGX-3100 and INO-9012. 5. Ensure the contents of the “mixing” vial are well mixed by gently inverting the vial several times. 6. Using a 3 mL syringe with a 1.5” 21 gauge needle, withdraw 1.1 mL of VGX- 3100 and INO-9012 from the “mixing” vial. This syringe will be used for dosing of subjects. Formulation Instruction Set B (exactly 1.1 mL VGX-3100 withdrawn): 1. Inject 1.1 mL of VGX- 3100 into an empty sterile vial; set this “mixing” vial which now contains 1.1 mL of VGX -3100 aside. 2. Using a new 0.5 or 1.0 mL syringe with a 1.5” needle, withdraw 0.11 mL from the vial SynConTM INO-9012 and add the 0.11 mL to the “mixing” vial containing 1.1 mL of VGX- 3100. The final volume of this vial should now be approximately 1.21 mL of VGX - 3100 and INO-9012. 3. Ensure the contents of the “mixing” vial are well mixed by gently inverting the vial several times. 4. Using a 3 mL syringe with a 1.5” 21 gauge needle, withdraw 1.1 mL of VGX- 3100 and INO-9012 from the “mixing” vial. This syringe will be used for dosing of subjects. Formulation Instruction Set C (1.2 mL or more of VGX-3100 withdrawn): 1. Inject 1.2 mL of VGX- 3100 into an empty sterile vial; set this “mixing” vial which now contains 1.2 mL of VGX -3100 aside. 2. Using a new 0.5 or 1.0 mL syringe with a 1.5” needle, withdraw 0.12 mL from the vial SynConTM INO-9012 and add the 0.12 mL to the “mixing” vial containing 1.2 mL of VGX- 3100. The final volume of this vial should now be approximately 1.32 mL of VGX - 3100 and INO-9012. 3. Ensure t he contents of the “mixing” vial are well mixed by gently inverting the vial several times. 4. Using a 3 mL syringe with a 1.5” 21 gauge needle, withdraw 1.1 mL of VGX- 3100 and INO-9012 from the “mixing” vial. This syringe will be used for dosing of subjects. Replace the 1.5” needle with 2” 21 gauge needle of the syringe for dosing of subjects. The syringe must be labeled with a four -hour expiration time from the time the vial is removed from the freezer. The label should also contain the words “administer as soon as possible”. 5.3.6 Return or Destruction of Study Drug Upon completion or termination of the study, all unused and/or partially used investigational product must be returned to Inovio Pharmaceuticals, Inc., or its designee, if not authorized by Inovio Pharmaceuticals, Inc. to be destroyed at the site. All investigational products returned to Inovio Pharmaceuticals, Inc., or its designee, must be accompanied by the appropriate documentation. Returned supplies should be in the original containers. Empty containers should not be returned to Inovio Pharmaceuticals, Inc. It is the Investigator’s responsibility to arrange for 34 Date: 8 April 2016 v 2.1 INO-3112 UPCC # 39313 / Inovio HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol disposal for all empty containers, provided that procedures for proper disposal have been established according to applicable federal, state, local and institutional guidelines and procedures, and provided that appropriate records of disposal are kept. The return of unused investigational product(s) should be arranged by the responsible Study Monitor. If investigational products are to be dest royed on site, it is the Investigator’s responsibility to ensure that arrangements have been made for the disposal, written authorization has been granted by Inovio Pharmaceuticals, Inc., or its designee, procedures for proper disposal have been establishe d according to applicable regulation and guidelines and institutional procedures, and appropriate records of the disposal have been documented. The unused investigational products can only be destroyed after being inspected and reconciled by the responsibl e Inovio Pharmaceuticals, Inc. representative. 5.4 Use of CELLECTRA Electroporation Device The instructions for use of the CELLECTRA device are located in the Operations Manual. Each clinical site will receive training for the use of the CELLECTRA device. The following specifications will be used during the study: Number of pulses per treatment = 3 Maximum Current Strength = 0.5 Amperes Maximum Voltage Strength = 200 Volts Electroporation pulse duration = 52 milliseconds/pulse Interval separating pulses = 1 second EP needle array length (injection depth) ~ 12 mm (with array guide in place) ~18 mm (without array guide) 5.4.1 Investigational Device Accountability Each clinical site is responsible for maintaining investigational device accountability. This includes recording the CELLECTRA ®5P serial number, applicator serial number, and array lot number used for electroporatio n of each subject. 6 Study Procedures and Treatments 6.1 Cohort I Immunotherapy will be performed prior to and after definitive surgery. Up to 2 doses may be administered approximately once every 3 weeks (+/-3 days), depending on the planned interval between pre- surgery evaluation and definitive surgery according to standard practice. Up to 3 doses will be given post- surgery. All subjects will receive a total of 4 doses of immunotherapy. 6.1.1 Pre treatment evaluation (Screening; Done Within 28 days of First Dose) 1. Signe d written informed consent. 2. Complete medical history including prior and current medications/treatments. 3. Complete physical examination including, but not limited to vital signs, height, weight and oxygen saturation. 4.