The purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional evaluation for an underlying etiology. 8.1.7 Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg or greater (≥5 times the indicated dose). No specific information is available on the treatment of overdose of pembrolizumab. Appropriate supportive treatment should be provided if clinically indicated. In the event of overdose, the subject should be observed closely for signs of toxicity. Appropriate supportive treatment should be provided if clinically indicated. If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are met. If a dose of Merck’s product meeting the protocol definition of overdose is taken without any associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non- serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional overdose without adverse effect.” All reports of overdose with and without an adverse event must be reported within 24 hours to the Sponsor. 79 Abbreviated Title: GBM Pembro HSPPC Version Date: 03/26/2024 8.2 ASSESSMENT OF S AFETY EVENTS AE information collected will include event description, date of onset, assessment of severity and relationship to study product and alternate etiology (if not related to study product), date of resolution of the event, seriousness and outcome. The assessment of severity and relationship to the study product will be done only by those with the training and authority to make a diagnosis and listed on the Form FDA 1572 as the site principal investigator or sub-investigator. AEs occurring during the collection and reporting period will be documented appropriately regardless of relationship. AEs will be followed through resolution. SAEs will be: Assessed for severity and relationship to study product and alternate etiology (if not related to study product) by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator. Recorded on the appropriate SAE report form, the medical record and captured in the clinical database. 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 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 section 8.2. SAE reports will be submitted to the NCI Center for Cancer Research (CCR) at: OSROSafety@mail.nih.gov and to the BTTC 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 SAFETY R EPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 8.4.1 To be Sent by OSRO Safety OSRO Safety will only provide the following: SAEs, SUSARs, overdoses and pregnancies. OSRO Safety will not send routine AEs or periodic reports. 80 Abbreviated Title: GBM Pembro HSPPC Version Date: 03/26/2024 8.4.2 To be Sent by BTTC study team 8.4.2.1 Adverse Events An investigator who is a qualified physician, will evaluate all adverse events. 8.4.2.2 Duration Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units. 8.4.2.3 Action taken Did the adverse event cause Merck product to be discontinued? 8.4.2.4 Relationship to Merck Product Did Merck product cause the adverse event? The determination of the likelihood that Merck product caused the adverse event will be provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the available information. The following components are to be used to assess the relationship between Merck product and the AE; the greater the correlation with the components and their respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 8.4.2.5 Exposure Is there evidence that the subject was actually exposed to Merck product such as: reliable history, acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 8.4.2.6 Time Course Did the AE follow in a reasonable temporal sequence from administration of Merck product? Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 8.4.2.7 Likely Cause Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors 8.4.2.8 Dechallenge Was Merck product discontinued or dose/exposure/frequency reduced? If yes, did the AE resolve or improve?