Pregnancy itself is not regarded as an S AE. However, congenital abnormalities or birth defects and spontaneous miscarriages that meet serious criteria (Section 8.1.3) 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 2 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 REPORTING FOR STUDIES CONDUCTED 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 in expedited manner to the FDA in accordance to 21 CFR 31.2.32. 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 S PONSOR 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 74 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 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 PLAN 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. T he first activity is before the study start s 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 occur at the study site. 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 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 S TATISTICAL HYPOTHESIS The primary objective of this trial is to determine the objective response rate of combination immunotherapy in participants with HPV associated malignancies. A secondary hypothesis (objective) will be to obtain preliminary data on duration of response, PFS, OS and ratio of 75 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 participants that are hospitalized because of adverse events attributed to disease progression. An exploratory hypothesis (objective) will be to evaluate exploratory immunologic studies to understand and improve the administered treatment. In patients with cervical cancer with prior pelvic radiation and boost brachytherapy, a key secondary objective is to evaluate the safety of the combination at a reduced dose level in these patients where a potential higher risk of grade 3 hematuria may exist with the full starting doses of M7824 at 1200 mg and NHS-IL12 at 16.8 mcg/kg. 10.2 SAMPLE SIZE DETERMINATION Data from the ongoing trial indicates that a response rate for M7824 may be approximately 30%. In the main study cohort (Cohort 1), t his trial will try to demonstrate if the proposed combination therapies may be associated with an improved response rate. The trial will treat participants with HPV related cancers with HPV vaccine + M7824 + NHS - IL12. The objective is to determine if this treatment can be associated with an acceptable response rate. To establish the efficacy of this combination treatment, the primary objective would be to determine if using the proposed agents would rule out a 30% response rate and result in a response rate consistent with 60%. As such, this trial in participants with HPV associated malignancies will be conducted using a Simon optimal two -stage phase II trial design (Simon R, Controlled Clinical Trials 10:1 -10, 1989) to rule out an unacceptably low PR+CR rate of 30% (p0=0.30) in favor of an improved response rate of 60% (p1=0.60). With alpha=0.10 (probability of accepting a poo r treatment=0.10) and beta = 0.10 (probability of rejecting a good treatment=0.10), the first stage will enroll 8 evaluable checkpoint naïve participants , and if 0 to 2 of the 8 have a clinical response, then no further participants will be accrued. If 3 o r more of the first 8 checkpoint naïve participants have a response, then accrual would continue until a total of 20 evaluable checkpoint naïve participants have been treated. As it may take up to several months to determine if a patient has experienced a response, a temporary pause in the accrual may be necessary to ensure that enrollment to the second stage is warranted. If there are 3 to 8 checkpoint naïve participants with a response out of 20 participants , this would be an uninterestingly low response rate. If there were 9 or more of 20 (45.0%) checkpoint naïve patients who experienced a response, this would be sufficiently interesting to warrant possible further study of the combination in later trials in this disease type; decisions about future use of the combination will incorporate response as well as toxicity profile information. Under the null hypothesis (30% response rate), the probability of early termination is 55.2%. In the cohort with patients with cervical cancer with prior pelvic radiation and boost brachytherapy where a potential higher risk of grade 3 hematuria may exist with the full starting doses of M7824 at 1200 mg and NHS -IL12 at 16.8 mcg/kg, the safety evaluation may require up to 12 patients as outlined in S ection 3.4.3, and if there are preliminary hints of efficacy within these 12 patients, up to 12 additional patients may be enrolled at the dose found to be safe for these patients to further explore the safety as well as the potential response rate in a small number of patients. It is expected that if 2 participants per month enroll on the trial, in order to enroll up to a total of 20 evaluable participants with checkpoint naïve disease in the main cohort, and 12+12=24 maximum in the patients in cohort 2, up to 3 years may be required. To allow for several inevaluable participants for the primary objective and potential replacements based on HPV status the accrual ceiling will be set at 56 participants. If additional patients are required to enroll on the 76 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 trial to account for screen failures and inevaluable patients, th e ceiling increase will be incorporated in an amendment. 10.3 POPULATIONS FOR ANALYSES All participants who receive any investigational treatment will be evaluable for safety and toxicity evaluations. All participants will be evaluable for toxicity from the time of their first treatment with any agent. For efficacy, a modified intention to treat population will be used. 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 Participants will be evaluated with respect to the grades and types of toxicities obtained. The results will be presented descriptivel y and tabled if appropriate. Further planned analyses are described below. 10.4.2 Analysis of the Primary Endpoints The percentage of checkpoint naïve subjects whose initial doses of study drugs are not modified that achieve an objective confirmed complete or partial overall tumor response using RECIST Version 1.1 will be evaluated. If anti -tumor responses are observed, the 95% confidence interval of the response rate will be evaluated. 10.4.3 Analysis of the Secondary Endpoints Data will be obtained on duration of response, PFS , OS and ratio of participants that are hospitalized because of adverse events attributed to disease progression. In addition, patients in cohort 2 will have their safety evaluated based on the description in Section 3.4.3. 10.4.3.1 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. 10.4.3.2 Progression-Free Survival PFS 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. Subjects who do not have disease progression or have not died at the end of follow up will be censored at the last known date the subject was progression free. 10.4.3.3 Objective Response Objective response is a complete or partial radiographic response as defined by RECIST 1.1 (Section 6.3.5). 77 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 10.4.3.4 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).