*** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression. Note: Patients with 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 Patients with Non-Measurable Disease (i.e., Non-Target Disease) 5.3.6 Duration of Response Duration of overall 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 recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). 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.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 48 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 Duration of stable disease: Stable 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. 5.3.7 Time to Progression Time to progression (TTP) is defined as the duration of time from start of treatment to time of disease progression. 5.4 TOXICITY CRITERIA The following adverse event management guidelines are intended to ensure the safety of each patient while on the study. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 6 NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN 6.1 DEFINITIONS Please refer to definitions provided in Policy 801: Reporting Research Events found here. 6.2 OHSRP OFFICE OF COMPLIANCE AND TRAINING/ IRB REPORTING 6.2.1 Expedited Reporting Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported per these policies. 6.2.2 IRB Requirements for PI Reporting at Continuing Review Please refer to the reporting requirements in Policy 801: Reporting Research Events found here. 6.3 NCI CLINICAL DIRECTOR R EPORTING Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical Director. A separate submission is not necessary as reports in iRIS will be available to the Clinical Director. In addition to those reports, all deaths that occur within 30 days after receiving a research intervention should be reported via email to the Clinical Director unless they are due to progressive disease. To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death. 6.4 INSTITUTIONAL BIOSAFETY C OMMITTEE (IBC) REPORTING CRITERIA 6.4.1 Serious Adverse Event Reports to IBC The Principal Investigator (or delegate) will notify IBC of any unexpected fatal or life- threatening experience associated with the use of PSA-TRICOM Vaccine as soon as possible but in no event later than 7 calendar days of initial receipt of the information. Serious adverse events 49 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 that are unexpected and associated with the use of the PSA-TRICOM Vaccine, but are not fatal or life-threatening, much be reported to NIH IBC as soon as possible, but not later than 15 calendar days after the investigator’s initial receipt of the information. Adverse events may be reported by using the FDA Form 3500a. 6.4.2 Annual Reports to IBC Within 60 days after the one-year anniversary of the date on which the IBC approved the initial protocol, and after each subsequent anniversary until the trial is completed, the Principal Investigator (or delegate) shall submit the information described below. Alternatively, the IRB continuing review report can be sent to the IBC in lieu of a separate report. Please include the IBC protocol number on the report. 6.4.2.1 Clinical Trial Information A brief summary of the status of the trial in progress or completed during the previous year. The summary is required to include the following information: the title and purpose of the trial clinical site the Principal Investigator clinical protocol identifiers participant population (such as disease indication and general age group, e.g., adult or pediatric); the total number of participants planned for inclusion in the trial; the number entered into the trial to date whose participation in the trial was completed; and the number who dropped out of the trial with a brief description of the reasons the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, or fully completed, if the trial has been completed, a brief description of any study results. 6.4.2.2 Progress Report and Data Analysis Information obtained during the previous year's clinical and non-clinical investigations, including: a narrative or tabular summary showing the most frequent and most serious adverse experiences by body system a summary of all serious adverse events submitted during the past year a summary of serious adverse events that were expected or considered to have causes not associated with the use of the gene transfer product such as disease progression or concurrent medications if any deaths have occurred, the number of participants who died during participation in the investigation and causes of death 50 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 a brief description of any information obtained that is pertinent to an understanding of the gene transfer product’s actions, including, for example, information about dose-response, information from controlled trials, and information about bioavailability. 6.5 NIH REQUIRED DATA AND SAFETY MONITORING PLAN 6.5.1 Principal Investigator/Research Team The Principal Investigator, lead associate investigator and the research nurse will meet at least weekly at each clinic to review all adverse events for each subject in this trial and to determine dose limiting toxicities and escalation rules. Unexpected adverse events and/or serious adverse events will be reported to the NIH’s Institutional Review Board (IRB) and sponsor/FDA as outlined above. If trends are noted and/or risks warrant it, accrual will be interrupted, dose levels expanded and/or the protocol and/or consent will be modified accordingly. 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 6.2.1 will be submitted within the appropriate timelines. The principal investigator will review adverse event and response data on each patient 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. 6.5.2 Safety Monitoring Committee (SMC) This protocol will be periodically reviewed by an intramural Safety Monitoring Committee (SMC). Initial review will occur as soon as possible after the annual NIH Intramural IRB continuing review date. Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting schedule permits or more frequently as may be required by the SMC based on the risks presented in the study. For initial and subsequent reviews, protocols will not be reviewed if there is no accrual within the review period. The SMC review will focus on unexpected protocol-specific safety issues that are identified during the conduct of the clinical trial. Written outcome letters will be generated in response to the monitoring activities and submitted to the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI. SMC concluded their oversight of the study on 12/20/2016 when the study closed to accrual. 7 SPONSOR PROTOCOL SAFETY REPORTING 7.1 DEFINITIONS 7.1.1 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)). 51 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 7.1.2 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 7.1.3) Inpatient hospitalization or prolongation of existing hospitalization oA 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 in health, is not considered a serious adverse event. oA hospitalization/admission that is solely driven by non-medical reasons (e.g., hospitalization for patient convenience) is not considered a serious adverse event.