Upon referral to the NIH, patients will be rapidly screened, and enrolled on the protocol, if appropriate. This trial will enroll patients in three arms sequentially to permit safety evaluation before adding the next agent. In the first arm of 12 patients, M7824 (1200 mg) will be administered intravenously on day 1 and 15. If no safety concerns, accrual will proceed to the 2nd arm, and 12 patients will enroll with M7824 (1200mg; intravenous) treatment on day 1 and 15 and TriAd vaccine (5 x 1011 VP; subcutaneous) treatment on day 1 only. If no safety concerns, accrual will proceed to the 3rd arm, and 12 patients will enroll with M7824 ((1200mg; intravenous) treatment on day 1 and 15 plus TriAd vaccine (5 x 1011 VP; subcutaneous injection) and N-803 (15mcg/kg, subcutaneously) treatment on day 1. After obtaining pre-treatment biopsies, imaging and blood collection, patients will receive the neoadjuvant immunotherapy at the NIH Clinical Center. Patients will then be sent back to their referring providers for their definitive standard of care surgery and adjuvant therapy as indicated based upon pathologic analysis of the surgical specimen. NCI investigators will have no role in directing the ensuing standard of care surgeries performed at outside institutions. For consistency in pathologic analysis of resection specimens, tissue blocks and/or slides will be obtained from outside institutions and be reviewed by the NCI Laboratory of Pathology. It is expected that up to 20 patients may enroll in one year. Thus, with 3 arms of 12 patients apiece, up to 36 evaluable patients may enroll. Accrual is expected to be completed within 2 years. 4 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 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 ................................................................................................8 2 ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................19 2.1 Eligibility Criteria ...........................................................................................................19 2.2 Screening Evaluation ......................................................................................................22 2.3 Participant Registration and Status Update Procedures..................................................23 2.4 Baseline Evaluation.........................................................................................................24 3 STUDY IMPLEMENTATION ..........................................................................................25 3.1 Study Design...................................................................................................................25 3.2 Drug Administration .......................................................................................................28 3.3 Dose Modifications .........................................................................................................29 3.4 Study Calendar................................................................................................................33 3.5 Cost and Compensation ..................................................................................................38 3.6 Criteria for Removal from Protocol Therapy and Off Study Criteria.............................38 4 CONCOMITANT MEDICATIONS/MEASURES............................................................39 4.1 General guidance.............................................................................................................39 4.2 N-803 ..............................................................................................................................39 5 BIOSPECIMEN COLLECTION........................................................................................41 5.1 Correlative Studies for Research/Pharmacokinetic Studies............................................41 5.2 Sample Storage, Tracking and Disposition.....................................................................45 5.3 Samples for Genetic/Genomic Analysis .........................................................................49 6 DATA COLLECTION AND EVALUATION ..................................................................49 6.1 Data Collection ...............................................................................................................49 6.2 Data Sharing Plans ..........................................................................................................50 6.3 Response Criteria ............................................................................................................51 6.4 Toxicity Criteria..............................................................................................................57 5 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 7 NIH REPORTING REQUIREMENTS/DATA SAFETY MONITORING PLAN ...........57 7.1 Definitions.......................................................................................................................57 7.2 OHSRP Office of Compliance and Training / IRB Reporting........................................57 7.3 NCI Clinical Director Reporting.....................................................................................57 7.4 Institutional Biosafety Committee (IBC) Reporting Criteria..........................................58 7.5 NIH Required Data and Safety Monitoring Plan ............................................................59 8 Sponsor protocol/Safety Reporting.....................................................................................60 8.1 Definitions.......................................................................................................................60 8.2 Assessment of Safety Events ..........................................................................................61 8.3 Reporting of Serious Adverse Events .............................................................................62 8.4 Waiver of expedited reporting to CCR ...........................................................................62 8.5 Safety Reporting Criteria to the Pharmaceutical Collaborators......................................62 8.6 Reporting Pregnancy.......................................................................................................62 8.7 Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND...................63 8.8 Sponsor Protocol Deviation Reporting ...........................................................................63 9 CLINICAL MONITORING...............................................................................................64 10 STATISTICAL CONSIDERATIONS ...............................................................................64 10.1 Statistical Hypothesis ..................................................................................................64 10.2 Sample Size Determination .........................................................................................65 10.3 Populations for analysis...............................................................................................65 10.4 Statistical analysis .......................................................................................................66 11 COLLABORATIVE AGREEMENTS...............................................................................67 11.1 Cooperative Research and Development Agreement (CRADA) ................................67 12 HUMAN SUBJECTS PROTECTIONS.............................................................................67 12.1 Rationale For Subject Selection ..................................................................................67 12.2 Participation of Children .............................................................................................68 12.3 Participation of Subjects Unable to Give Consent ......................................................68 12.4 RISK/Benefits Assessment..........................................................................................68 12.5 Consent Process and Documentation ..........................................................................70 13 REGULATORY AND OPERATIONAL CONSIDERATIONS.......................................71 13.1 Study Discontinuation and Closure.............................................................................71 13.2 Quality Assurance and Quality Control ......................................................................72 6 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 13.3 Conflict of Interest Policy ...........................................................................................72 13.4 Confidentiality and Privacy.........................................................................................72 14 PHARMACEUTICAL INFORMATION ..........................................................................73 14.1 ETBX 011, 051, 061....................................................................................................73 14.2 M7824 (Bintrafusp alfa, MSB0011359C)...................................................................77 14.3 N-803 (ALT-803) ........................................................................................................80 15 REFERENCES ...................................................................................................................83 Appendix A: -Performance Status Criteria....................................................................................86 7 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 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.