It is expected that up to 22 participants may enroll. Phase II: Newly diagnosed p16-positive oropharyngeal cancer: Evaluation of HPV vaccine alone (Arm 2A: Stage I (T1,T2 N1)/II/III) as neoadjuvant/ induction therapy before definitive standard of care therapy. Participants will receive neoadjuvant/ induction immunotherapy at NIH Clinical Center and then be referred back to their home institution for definitive standard of care therapy. It is expected that up to 20 participants may enroll. Newly diagnosed stage II/III/IVA/IVB HPV-SNSCC: Enrollment and treatment will occur similarly as participants with p16+ oropharyngeal cancer for exploratory correlates to advise possible future trials. Up to 2 participants may enroll in this group. 4 Abbreviated Title: Combo Immunotx in HPV OPSCC Version Date: 04.25.2023 TABLE OF CONTENTS PRÉCIS............................................................................................................................................2 TABLE OF CONTENTS ................................................................................................................4 STATEMENT OF COMPLIANCE ................................................................................................7 1 INTRODUCTION ...................................................................................................................8 1.1 Study Objectives ...............................................................................................................8 1.2 Background and Rationale ................................................................................................9 2 ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................20 2.1 Eligibility Criteria ...........................................................................................................20 2.2 Screening Evaluation ......................................................................................................23 2.3 Participant Registration and Status Update Procedures..................................................24 2.4 Baseline Evaluation.........................................................................................................25 3 STUDY IMPLEMENTATION .............................................................................................27 3.1 Study Design...................................................................................................................27 3.2 Drug Administration .......................................................................................................29 3.3 Dose Modifications .........................................................................................................30 3.4 Study Calendar................................................................................................................39 3.5 Cost and Compensation ..................................................................................................45 3.6 Criteria for Removal from Protocol Therapy and Off Study Criteria.............................45 4 CONCOMITANT MEDICATIONS/MEASURES...............................................................46 4.1 Permitted Medications ....................................................................................................46 4.2 Prohibited Medications ...................................................................................................46 5 CORRELATIVE STUDIES FOR RESEARCH ...................................................................48 5.1 Biospecimen Collection ..................................................................................................48 5.2 Sample Storage, Tracking and Disposition.....................................................................52 6 DATA COLLECTION AND EVALUATION .....................................................................55 6.1 Data Collection ...............................................................................................................55 6.2 Data Sharing Plans ..........................................................................................................56 6.3 Response Criteria ............................................................................................................56 6.4 Toxicity Criteria..............................................................................................................63 7 NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN...63 7.1 Definitions.......................................................................................................................63 5 Abbreviated Title: Combo Immunotx in HPV OPSCC Version Date: 04.25.2023 7.2 OHSRP Office of Compliance and Training / IRB Reporting........................................63 7.3 NCI Clinical Director Reporting.....................................................................................64 7.4 Institutional Biosafety Committee (IBC) Reporting Criteria..........................................64 7.5 NIH Required Data and Safety Monitoring Plan ............................................................65 8 SPONSOR PROTOCOL / SAFETY REPORTING..............................................................66 8.1 Definitions.......................................................................................................................66 8.2 Assessment of Safety Events ..........................................................................................67 8.3 Reporting of Serious Adverse Events .............................................................................68 8.4 Waiver of Expedited Reporting to CCR .........................................................................68 8.5 Safety Reporting Criteria to the Pharmaceutical Collaborators......................................68 8.6 Reporting Pregnancy.......................................................................................................68 8.7 Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND...................69 8.8 Sponsor Protocol Deviation Reporting ...........................................................................69 9 CLINICAL MONITORING..................................................................................................70 10 STATISTICAL CONSIDERATIONS ..................................................................................70 10.1 Statistical Hypothesis ..................................................................................................70 10.2 Sample Size Determination .........................................................................................71 10.3 Populations for Analyses.............................................................................................72 10.4 Statistical Analyses......................................................................................................72 11 COLLABORATIVE AGREEMENTS..................................................................................74 11.1 Cooperative Research and Development Agreement (CRADA) ................................74 12 HUMAN SUBJECTS PROTECTIONS................................................................................74 12.1 Rationale For Subject Selection ..................................................................................74 12.2 Participation of Children .............................................................................................74 12.3 Participation of Subjects Unable to Give Consent ......................................................74 12.4 Risk/Benefit Assessment.............................................................................................75 12.5 Consent Process and Documentation ..........................................................................77 13 REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................78 13.1 Study Discontinuation and Closure.............................................................................78 13.2 Quality Assurance and Quality Control ......................................................................79 13.3 Conflict of Interest Policy ...........................................................................................79 13.4 Confidentiality and Privacy.........................................................................................79 6 Abbreviated Title: Combo Immunotx in HPV OPSCC Version Date: 04.25.2023 14 PHARMACEUTICAL INFORMATION .............................................................................80 14.1 PRGN-2009 (IND #19628) .........................................................................................80 14.2 M7824 (IND #19628 ).................................................................................................85 15 REFERENCES ......................................................................................................................89 16 APPENDIX A: Performance Status Criteria .........................................................................94 7 Abbreviated Title: Combo Immunotx in HPV OPSCC Version Date: 04.25.2023 STATEMENT OF COMPLIANCE The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical Practice (ICH GCP) and the following: United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects Protection and ICH GCP Training. The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted to the Institutional Review Board (IRB) for review and approval.