Followed through resolution by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator. For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events recorded from the time of first investigational product administration must be reported to the sponsor with the exception of any listed in section 8.4.. 8.3 REPORTING OF SERIOUS A DVERSE EVENTS Any AE that meets a protocol-defined serious criteria or meets the definition of Adverse Event of Special Interest that require expedited reporting must be submitted immediately (within 24 hours of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited reporting requirements are found in section 8.4. All SAE reporting must include the elements described in 8.2. SAE reports will be submitted to the Center for Cancer Research (CCR) at: OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. CCR SAE report form and instructions can be found at: https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions Following the assessment of the SAE by OSRO, other supporting documentation of the event may be requested by the OSRO Safety and should be provided as soon as possible. 8.4 WAIVER OF EXPEDITED REPORTING TO CCR As death due to disease progression is part of the study objectives (OS), and captured as an endpoint in this study, it will not be reported in an expedited manner to the sponsor. However, if there is evidence suggesting a causal relationship between the study drug and the event, report the event in an expedited manner according to section 8.3. 8.5 SAFETY R EPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS Reporting will be per the collaborative agreements. 8.6 REPORTING PREGNANCY All required pregnancy reports/follow-up to OSRO will be submitted to: OSROSafety@mail.nih.gov. Forms and instructions can be found here: https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions. 8.6.1 Maternal exposure If a patient becomes pregnant during the course of the study, the study treatment should be discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 63 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later than 24 hours of when the outcome of the Pregnancy becomes known, Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects and spontaneous miscarriages that meet serious criteria (8.1.2) should be reported as SAEs. The outcome of all pregnancies should be followed up and documented. 8.6.2 Paternal exposure Male patients should refrain from fathering a child or donating sperm during the study and for 2 months after the last dose of any investigational drug on this protocol, whichever occurs later. Pregnancy of the patient’s partner is not considered to be an AE. The outcome of all pregnancies occurring from the date of the first dose until 2 months after the last dose should, if possible, be followed up and documented. Pregnant partners may be offered the opportunity to participate in an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry study) to provide data about the outcome of the pregnancy for safety reporting purposes. 8.7 REGULATORY R EPORTING FOR STUDIES C ONDUCTED UNDER CCR-S PONSORED IND Following notification from the investigator, CCR, the IND sponsor, will report any suspected adverse reaction that is both serious and unexpected. CCR will report an AE as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the study product and the adverse event. CCR will notify FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or under any investigator’s IND) in an IND safety report of potential serious risks from clinical trials or any other source, as soon as possible, in accordance to 21 CFR Part 312.32. All serious events will be reported to the FDA at least annually in a summary format. 8.8 SPONSOR PROTOCOL DEVIATION REPORTING A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual of Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or protocol-specific procedural requirements on the part of the participant, the Investigator, or the study site staff inclusive of site personnel performing procedures or providing services in support of the clinical trial. It is the responsibility of the study Staff to document any protocol deviation identified by the Staff or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online application. The entries into the PDTS online application should be timely, complete, and maintained per CCR PDTS user requirements. In addition, any deviation to the protocol should be documented in the participant’s source records and reported to the reviewing IRB per their guidelines. OSRO required protocol deviation reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol deviations. 64 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 9 CLINICAL MONITORING Clinical site monitoring is conducted to ensure that the rights of the participants are protected, that the study is implemented per the approved protocol, Good Clinical Practice and standard operating procedures, and the quality and integrity of study data and data collection methods are maintained. Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable regulatory requirements. Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human subject protections and integrity of the study data. OSRO will determine the intensity and frequency of monitoring based on several factors, including study type, phase, risk, complexity, expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger CMP updates. OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit (SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) (IMVs), and a study Close-Out Visit (COV). Some monitoring activities may be performed remotely, while others will take place at the study site(s). Monitoring visit reports will describe visit activities, observations, and associated action items or follow-up required for resolution of any issues, discrepancies, or deviations. Monitoring reports will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, coordinating center (if applicable) and the Sponsor regulatory file. The site Monitor will inform the study team of any deviations observed during monitoring visits. If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR Protocol Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as applicable per institutional and IRB guidance. 10 STATISTICAL CONSIDERATIONS 10.1 STATISTICAL HYPOTHESIS 10.1.1 Primary Endpoint(s): The primary endpoint of this study is to determine if by using any of the three proposed treatments: M7824 alone, M7824 plus TriAd vaccine, or M7824 plus TriAd vaccine plus N803, there is a sufficiently high success rate in patients with head and neck cancer. Success is defined as pathologic complete response (pCR) or clinical to pathologic downstaging in each patient. 10.1.2 Secondary Endpoint(s): Estimate the rate of grade 3 or 4 immune related adverse events (irAEs) 65 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 Determine the rate of treatment-related adverse events (AE) causing a delay of 4 weeks or more beyond planned surgery Estimate the response rate of the primary disease by CT imaging (RECIST) Estimate the one- and two-year recurrence free survival One- and two-year overall survival 10.2 SAMPLE SIZE D ETERMINATION Based on prior reports for single agents, no pCRs but an overall 30% success rate may be anticipated. Because of uncertainty involving delays in surgery following each treatment arm, the following three arms will be enrolled sequentially to permit safety evaluation before adding the next agent: M7824 alone M7824 + Vaccine M7824 + Vaccine + N-803 The trial will begin by enrolling 12 patients to the M7824 alone arm (arm A). For sample size estimation purposes, with 12 patients, there would be 81% power for an exact binomial test with a one-sided 0.10 significance level to detect the difference between a 20% success rate and a 50% success rate in this arm. If 0-1 of the 12 patients experiences a dose limiting toxicity, accrual will then proceed to the 2nd arm (arm B), and 12 patients will enroll following the same criteria. Finally, if 0-1 of 12 patients experiences a dose limiting toxicity while treated in the second arm (arm B), accrual will proceed to the 3rd arm (arm C), again with 12 patients enrolled. After completion of the 3 arms of 12 patients apiece, the success rates will be evaluated in each arm. Because there is no knowledge of what the success rate of M7824 alone will be in this setting, a more definitive evaluation will first require these preliminary results to determine appropriate parameters for further investigation. Based upon the findings from these 3 limited size arms, including both the pCR rate and clinical downstaging, an amendment will detail the planned expansion as appropriate for A-C of the arms, using parameters derived from information obtained during the 12 patients enrolled initially in the trial. 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. To allow for a small number of inevaluable patients, the accrual ceiling will initially be set at 40 patients. 10.3 POPULATIONS FOR ANALYSIS Modified intention to treat. Any patients who receive at least one dose of any of the agents will be included in any toxicity or safety data reported. Patients who receive at least one dose of each of the intended agents on the three arms will be included in the analyses of primary and secondary endpoints. 66 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 10.4 STATISTICAL ANALYSIS 10.4.1 General approach If the arms can have 0-1 patients with dose limiting toxicity, the number of patients on each arm who have a pCR or who have clinical to pathologic downstaging will be determined and reported with a confidence interval. 10.4.2 Analysis of primary endpoints For each arm, the number of patients who experience a pCR will be determined and reported. In addition, for each arm, the fraction of patients who experience clinical to pathologic downstaging will be reported. Finally, for each arm, the fraction of patients who experience either a pCR or clinical to pathologic downstaging will be reported. Each of these fractions will be reported along with a 90% one-sided confidence interval. 10.4.3 Analysis of secondary endpoints The secondary endpoints and their intended analyses are as follows: To estimate the rate of grade 3 or 4 immune-related adverse events; the actual number of patients experiencing these events will be reported separately by arm. To determine the rate of patients whose surgery is delayed 4 weeks or greater beyond planned surgery will be reported as the number out of the patients per arm, separately by arm. To estimate the response rate of the primary disease by RECIST, the fraction with CR+PR out of evaluable patients will be reported along with a 95% confidence interval, by arm. To estimate the 1 year and 2-year RFS rates. A Kaplan-Meier curve of RFS will be constructed for each arm, with the 1- and 2-year values reported along with 95% confidence intervals. To estimate the 1 year and 2-year overall survival. A Kaplan-Meier curve of OS will be constructed for each arm, with the 1- and 2-year values reported along with 95% confidence intervals. 10.4.4 Safety analyses Data on adverse events for each arm will be obtained and reported: to estimate the rate of grade 3 or 4 immune-related adverse events; the actual number of patients experiencing these events will be reported separately by arm. 10.4.5 Baseline descriptive analyses Descriptive statistics will be determined and reported for patients enrolled onto any of the three treatment arms, separately by arm. 10.4.6 Planned interim analyses None. 67 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 10.4.7 Subgroup analyses None. 10.4.8 Tabulation of individual patient data None.