*** In exceptional circumstances, unequivocal progression in non- target lesions may be accepted as disease progression. Note : Participants wi th a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as “ symptomatic deterioration.” Every effort should be made to document the objective progression even after discontinuation of treatment. For P articipants with Non -Measurable Disease (i.e., Non -Target Disease) Non-Target Lesions New Lesions Overall Response CR No CR Non-CR/non- PD No Non-CR/non- PD* Not all evaluated No not evaluated Unequivocal PD Yes or No PD Any Yes PD * ‘Non -CR/non- PD’ is preferred over ‘stable disease’ for non -target disease since SD is increasingly used as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised 6.3.5.4 Duration of Response Duration of overall response : The dur ation 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 recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). 68 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented. Duration of stable disease : Stab le disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements. 6.3.5.5 Progression-Free Survival PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. 6.4 TOXICITY CRITERIA The following adverse event management guidelines are intended to ensure the safety of each participants while on the study. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm ). 7 NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN 7.1 DEFINITIONS Please refer to definitions provided in Policy 801: Reporting Research Events found at: https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance- 800Series- ComplianceandResearchEventReportingRequirements . 7.2 OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING 7.2.1 Expedited Reporting Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802 Non- Compliance Human Subjects Research found at:https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance -800Series-ComplianceandResearchEventReportingRequirements . Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported per these policies . 7.2.2 IRB Requirements for PI Reporting at Continuing Review Please refer to the reporting requirements in Policy 801: Reporting Research Events found at:https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance -800Series-ComplianceandResearchEventReportingRequirements . 7.2.3 NCI Clinical Director Reporting Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to the NCI Clinical Director /designee; therefore, a separate submission for these reports is not necessary. 69 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 In addition to those reports, all deaths that occur within 30 days after receiving a research intervention s hould be reported via email unless they are due to progressive disease. To report these deaths, please send an email describing the circumstances of the death to NCICCRQA@mail.nih.gov within one business day of learning of the death. 7.3 NIH REQUIRED DATA AND SAFETY MONITORING PLAN 7.3.1 Principal Investigator/Research Team The clinical research team will meet on a regular basis (approximately weekly) when participants are being actively treated on the trial to discuss ea ch participant . Decisions about dose level enrollment and dose escalation if applicable will be made based on the toxicity data from prior participants . All data will be collected in a timely manner and reviewed by the principal investigator or a lead associate investigator. Events meeting requirements for expedited reporting as described in Section 7.2.2 will be submitted within the appropriate timeline . The principal investigator will review adverse event and response data on each participant to ensure safety and data accuracy. The principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff. 7.3.2 Data Safety Monitoring Board (DSMB) (OSRO) The DSMB is an independent group of at least 3 experts that monitors participant safety and advises The Sponsor . DSMB members will be separate and independent of study staff participating in this trial and should not have scientific, financial, or other conflicts of interest related to this trial. The DSMB will consist of members with appropriate expertise to contribute to the interpretation of data from this trial. A quorum will consist of a simple majority. The DSMB will review cumulative safety data from this trial at least annually. The DSMB will meet as requested by the sponsor or PI. The DSMB will have a final review meeting at the end of the study. Procedures for DSMB reviews/meetings will be defined in the DSMB charter. The DSMB will review applicable data, including, but not limited to, enrollment, demographics, dosing data, clinical laboratory data, and safety data, at scheduled timepoints during this trial as defined in the DSMB charter. The DSMB will review blinded aggregate data in the open session of the DSMB meetings. Additional data may be requested by the DSMB , and interim statistical reports may be generated as deemed necessary and appropriate by the Sponsor. As an outcome of each review/meeting, the DSMB will make a recommendation as to the advisability of proceeding with study product administration, and to continue, modify, or terminate this trial. 70 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 8 SPONSOR PROTOCOL /SAFETY REPORTING 8.1 DEFINITIONS 8.1.1 Adverse Event Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (ICH E6 (R2)). 8.1.2 Adverse Event of Special Interest (AESI) Mucosal bleeding events which are at least possibly related to study drug (M7824) will be captured as AESIs. These events will not require expedited reporting to the study sponsor unless they also meet SAE criteria. 8.1.3 Serious Adverse Event (SAE) An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following: • Death ; • A life -threatening adverse event (see Section 8.1.4 ); • Inpatient hospitalization or prolongation of existing hospitalization o A hospitalization/admission that is pre -planned (i.e., elective or scheduled surgery arranged prior to the start of the study), a planned hospitalization for pre -existing condition, or a procedure required by the protocol, without a serious deterioration i n health, is not considered a serious adverse event. o A hospitalization/admission that is solely driven by non- medical reasons (e.g., hospitalization for patient convenience) is not considered a serious adverse event. o Emergency room visits or stays in observation units that do not result in admission to the hospital would not be considered a serious adverse event. The reason for seeking medical care should be evaluated for meeting one of the other serious criteria. • Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; • A congenital anomaly/birth defect; • Important medical events that may not result in death, be life -threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 71 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 8.1.4 Life-threatening An adverse event or suspected adverse reaction is considered "life -threatening" if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death (21CFR312.32). 8.1.5 Severity The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0. 8.1.6 Relationship to Study Product All AEs will have their relationship to study product assessed using the terms: related or not related. • Related – Ther e is a reasonable possibility that the study product caused the adverse event. Reasonable possibility means that there is evidence to suggest a causal relationship between the study product and the adverse event. • Not Related – Ther e is not a reasonable possibility that the administration of the study product caused the event. 8.1.7 Adverse Events of Special Interest (AESI) An adv erse event of special interest (AESI) is one of scientific and medical interest specific to understanding of the Investigational Product(s) and may require close monitoring and rapid communication by the investigator to the sponsor. An AESI may be serious or non- serious. The rapid reporting of AESIs allows ongoing surveillance of these events to characterize and understand them in association with the use of these investigational products. Only AESIs that match the definition of SAE will be reported as other SAEs within 24 hours from the knowledge of event. The following adverse events, regardless of site, will be collected as an AESI to enable evaluation of potential risk factors, such as site/past radiation/associated infection at site/recent instrumentation and other variables such as time to onset, exposure history, grade of bleeding, anatomical sites, etc. can be collected.