56 12.2 CONFLICT OF INTEREST .................................................................................................. 56 13 PUBLICATION PLAN .......................................................................................................56 14 LIST OF ABBREVIATION S .............................................................................................57 15 REFERENCES .....................................................................................................................59 6 Date: 8 April, 2016 v 2.1 INO-3112 UPCC # 39313 / HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol CLINIC AL PROTOCOL SYNOPSIS Title of Study: Prospective Study of HPV Specific Immunotherapy in Subjects with HPV Associated Head and Neck Squamous Cell Carcinoma (HNSCCa) Number of Study Centers and Countries/Regions: 1 Site (United States) Research Hypothes is: This protocol proposes to study the safety and the immune effects of immunotherapy with INO-3112 that contains VGX-3100, synthetic plasmid DNA encoding human papillomavirus ( HPV)-16 and HPV-18 E6/E7 antigens and INO-9012, a recombinant IL -12 molecular adjuvant administered. The safety and effects of immunotherapy will be studied in following two populations: 1. In chemo - and radiation-naïve subjects who undergo definitive surgery and 2. In subjects after chemoradiation therapy Study Objectives: Primary: Evaluate safety of treatment with INO -3112. Secondary: 1. Evaluate humoral and cellular immune response post to administration of INO -3112 in chemo - and radiation- naïve subjects who undergo definitive surgery: a. Pre- and Post -immunotherapy tissue analysis to evaluate infiltration of T cells in the tumor b. Evaluate effect of number of doses on immune responses c. Evaluate immune response duration 2. Evaluate humoral and cellular immune response to administration of INO -3112 in subjects after chemoradiation therapy : - Evaluate immune response duration Exploratory: 1. Explore anti -tumor response 2. Explore progression free survival 7 Date: 8 April, 2016 v 2.1 INO-3112 UPCC # 39313 / HPV -005 Inovio Pharmaceuticals, Inc Clinical Protocol Sample Size: A minimal of 20, and no more than 25 subjects will be enrolled in this study. Study Design: This will be a prospective, open- label, Phase I/IIa study of immunotherapy of INO -3112 in subjects with HPV -positive HNSCCa. Subjects will receive a course of treatment as described below and will be followed for safety as well as immune and clinical responses for 6 months from the last dose of immunotherapy. The safety and effects of immunotherapy will be studied in following two populations: 1. In chemo - and radiation-naïve subjects who undergo definitive surgery and 2. In subjects after chemoradiation therapy Doses of INO-3112 are based on safety experience in prior and on- going clinical trials. Based on the prior experience with these agents, dose escalation will not be conducted in this trial. The study is divided into the following treatment cohorts: I. INO-3112 (6 mg VGX -3100 + 1 mg INO -9012) will be given to subjects before and after definitive surgery II. INO-3112 (6 mg VGX- 3100 + 1 mg INO -9012) will be given to subjects after chemoradiation therapy Cohort I: Immunotherapy will be given both before and after definitive surgery. Each subject wi ll receive a total of 4 doses of treatment. Each treatment will be 6 mg of VGX - 3100 and 1 mg INO -9012 (INO -3112) delivered IM followed by electroporation (EP). A minimum of 5 eligible subjects will be enrolled to this cohort.