Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects and spontaneous miscarriages that meet serious criteria (Section 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 participants should refrain from fathering a child or donating sperm during the study and for two months after the last dose of M7824. Pregnancy of the participant’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 70 Abbreviated Title: Combo Immunotx in HPV OPSCC Version Date: 04.25.2023 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. 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 that 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 before the study starts is 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, findings of protocol non-adherence and associated action items or follow-up required for resolution of findings. Monitoring reports will be distributed to the study PI, NCI CCR QA, coordinating center (if applicable) and the OSRO 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 Endpoints 10.1.1.1 Phase I: The primary endpoint of the phase I portion of the study is to determine the recommended phase II dose (RP2D) of PRGN-2009 (HPV vaccine) alone and in combination with M7824. 71 Abbreviated Title: Combo Immunotx in HPV OPSCC Version Date: 04.25.2023 10.1.1.2 Phase II: The primary endpoint of the phase II portion of the study is to determine if HPV vaccine alone (Arm 2A) is able to result in a  2-fold increase in CD3+ tumor infiltrating T cells post treatment compared with pre-treatment in participants with p16+ oropharyngeal cancer. 10.1.2 Secondary Endpoints 10.1.2.1 Phase I: The secondary endpoint of the phase I portion of the study are to determine overall response rate (ORR), progression-free survival time (PFS), overall survival (OS), ratio of participants that are hospitalized because of adverse events attributed to disease progression, and duration of response of the combination therapy in participants with advanced disease. 10.1.2.2 Phase II: The secondary endpoints of the phase II portion of the study are: To determine if the use of HPV vaccine alone results in potentially prolonged survival as compared to the expected 80% three-year historical survival for this population. To determine the 3-year overall and relapse-free survival rate for HPV vaccine alone (Arm 2A) in combination with standard of care chemoradiation in participants with p16+ oropharyngeal cancer. 10.1.3 Exploratory Endpoints The exploratory endpoints of the Phase II portion of the study are: To determine if the use of HPV vaccine alone results in potentially prolonged survival as compared to the expected 80% three-year historical survival for this population. To determine the 3-year overall and relapse-free survival rate for HPV vaccine alone (Arm 2A) in combination with standard of care chemoradiation in HPV-SNSCC participants. 10.2 SAMPLE SIZE D ETERMINATION The phase I portion of the trial will be conducted using 3+3 dose escalation design evaluating the safety of PRGN-2009 at two dose levels as monotherapy and at the RP2D of PRGN-2009 in combination with a fixed dose of M7824. Using this design up to 22 participants may be enrolled on the phase I portion of the study. In arm 2A, phase II, 20 participants with p16+ oropharyngeal cancer will be enrolled based on the following reasoning. Assume that a success for any individual participant will be defined as that participant experiencing a two-fold increase in CD3+ tumor infiltrating T cells post treatment compared with pre-treatment. With 20 participants, there would be 80.4% power to detect a difference between 50% and 80% of participants experiencing a success in arm 2A, with an exact binomial test using a one-sided 0.05 significance level. As an illustration, with 20 participants, if 15 participants were able to have a two-fold increase, the lower two-sided 90% confidence bound on 15/20 is 54.4% and the upper two-sided 90% confidence bound is 89.6%. Thus, 15/20 participants would demonstrate the intended magnitude of effect. If 14/20 had this outcome, the lower 90% two-sided bound is 49.2% and the upper two-sided 90% bound is 86.0%, essentially demonstrating nearly the same result. 72 Abbreviated Title: Combo Immunotx in HPV OPSCC Version Date: 04.25.2023 Expecting that up to 22 evaluable participants will enroll on the phase I portion of the study, that 20 evaluable p16+ oropharyngeal cancer participants will enroll on phase II 2A, and that up to 2 evaluable HPV-SNSCC participants may enroll on phase II 2A, a total of up to 44 evaluable participants will be planned to enroll on this protocol. To allow for a few inevaluable participants the accrual ceiling for this protocol will be set at 50 participants. 10.3 POPULATIONS FOR ANALYSES All participants who receive any investigational treatment will be evaluable for safety and toxicity evaluations. For phase II, only HPV-OPC participants will be evaluable for primary and secondary objective endpoints. HPV-SNSCC participants will be evaluable only for exploratory objectives. For phase II, participants who receive at least two doses of therapy and have an adequate pretreatment and posttreatment biopsy will be evaluable for immune infiltration assessments. For phase II, participants who receive at least two doses of immunotherapy and go on to receive standard definitive therapy will be evaluable for relapse free survival and overall survival assessments. For phase I and II participants, only those participants who have measurable disease present at baseline and have had their disease re-evaluated will be considered evaluable for response. (Note: Participants who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) 10.4 STATISTICAL ANALYSES 10.4.1 General Approach The phase I portion of the study will be conducted as a safety assessment using a 3+3 dose escalation design. In addition, Arm 1B will be expanded to a total of 10 evaluable participants to gauge the preliminary efficacy of the combination of PRGN-2009 and M7824 in participants with advanced disease. The phase II portion of the study will be conducted to evaluate for a potentially significant increase in CD3+ tumor infiltrating lymphocytes with immunotherapy induction. 10.4.2 Analysis of the Primary Endpoints Regarding the phase I portion of the study, participants will be evaluated with respect to the grades and types of toxicities obtained. The results will be presented descriptively and tabled if appropriate. Regarding the phase II portion of the study the rate of doubling of baseline CD3+ tumor infiltrating lymphocytes will be provided as well as the 95% confidence interval. 10.4.3 Analysis of the Secondary Endpoints For the phase I portion of the study data will be obtained on ORR, duration of response, PFS, OS, and ratio of participants that are hospitalized because of adverse events attributed to disease progression. 10.4.4 Duration of Response The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that PD is objectively documented and is evaluated using the Kaplan-Meier method. 73 Abbreviated Title: Combo Immunotx in HPV OPSCC Version Date: 04.25.2023 10.4.4.1 Progression-Free Survival and Relapse-Free survival PFS and RFS will be evaluated using Kaplan-Meier methods. PFS will be defined as the time from the date of first treatment to the date of disease progression or death (any cause) whichever occurs first. RFS will be defined as the time from completion of standard chemoradiation to the date of disease recurrence or death (any cause) whichever occurs first. Subjects who do not have disease progression, disease recurrence or have not died at the end of follow up will be censored at the last known date the subject was progression or relapse free. 10.4.4.2 Objective Response Objective response is a complete or partial radiographic response as defined by RECIST 1.1 (Section 6.3.5). 10.4.4.3 Overall Survival OS will be evaluated using Kaplan-Meier methods. OS will be defined as the time from the date of first treatment to the date of death (any cause). Subjects who are alive at the end of follow up will be censored at the last known date alive. 10.4.5 Safety Analyses Safety endpoints will be analyzed as summary statistics during treatment and/or as change scores from baseline assessments. AEs will be coded as defined in the Medical Dictionary for Regulatory Activities (MedDRA). All AEs will be recorded and tabulated following each treatment. AEs will be recorded by severity, frequency, and relationship to the study intervention and will be presented by System Organ Class (SOC) designations and preferred term groupings. Information on each AE will include start date, stop date, severity, relationship, expectedness, outcome, and duration. Adverse events leading to premature discontinuation from the study intervention and serious treatment-emergent AEs will be presented either in a Table or a Listing. In addition, overall safety will be assessed by descriptive analyses using tabulated frequencies of AEs by grade using CTCAE Version 5 within dose cohorts and for the overall study population in terms of treatment-emergent AEs, SAEs, and clinically significant changes in safety laboratory tests, physical examinations, ECGs, and vital signs. 10.4.6 Baseline Descriptive Statistics Baseline Characteristics will be described. 10.4.7 Planned Interim Analyses Interim assessment of safety will be made based on DLT assessments according to the 3+3 dose escalation design in the phase I portion of the study and the first six participants enrolled on the phase II portion of the study. 10.4.8 Tabulation of Individual Participant Data Individual responses in a cohort may be depicted within a larger group using a waterfall plot or spider diagram. 10.4.9 Exploratory Analyses (Immune Responses) Where feasible, exploratory immune analyses will be conducted to evaluate anti-tumor immune responses. Immune response will be assessed among all subjects treated in each cohort. The 74 Abbreviated Title: Combo Immunotx in HPV OPSCC Version Date: 04.25.2023 magnitude of immune responses will be described. A subject will be considered evaluable for immune response if they receive at least one dose of treatment.