Toxicity data from the current dose level will be collected and reviewed to ensure that there were no severe toxicities that would preclude further patient enrollment. Patients will be treated with therapeutic intent and response to the therapy will be closely monitored. 12.5.1.2 Imaging risks The MRIs to be done in this study will involve contrast. The risks associated with MRIs and contrast are discussed in the consent form. Although MR imaging with gadolinium has been used as part of the standard care for patients with high grade gliomas, long term toxicities of gadolinium as a consequence of gadolinium accumulation in the body has been reported. All investigators will ascertain the MR imaging history of all prospective study participants to determine the extent of prior exposure to gadolinium contrast. Radiology will be consulted if there is a history of repeated gadolinium exposure. 12.5.1.3 Blood Collection The risk of blood draws in this study is that it may cause pain, bleeding, and/or bruising. The risks associated with blood collection are discussed in the consent form. Participants may faint and/or develop an infection with redness and irritation of the vein at the site where blood is drawn. Frequent blood collection may cause anemia (low red blood cell count), which may create a need for blood transfusions. 12.5.1.4 Questionnaires The risk of questionnaires in this study is that they may contain questions sensitive in nature. Participants may refuse to answer any question that makes them feel uncomfortable. The primary use of the information collected is to assess the severity of symptoms related to study treatment. Submission of this information is voluntary. 12.5.1.5 Non-Physical Risks of Genetic Research 12.5.1.5.1 Risk Of Receiving Unwanted Information 89 Abbreviated Title: GBM Pembro HSPPC Version Date: 03/26/2024 Anxiety and stress may arise as a result of the anticipation that unwanted information regarding disease related DNA sequencing or disease tendencies, or misattributed paternity. Patients will be clearly informed that the data related to DNA sequencing and genetic analysis is coded, investigational and will not be shared with patients, family members or health care providers. 12.5.1.5.2 Risk Related To Possibility That Information May Be Released This includes the risk that data related to genotype, DNA sequencing or risk for disease tendency or trait can be released to members of the public, insurers, employers, or law enforcement agencies. Although there are no plans to release results to the patients, family members or health care providers, this risk will be included in the informed consent document. 12.5.2 Benefits The potential benefit to a patient on this study is a reduction in the bulk of their tumor and improvement in cancer lesions, which may or may not have favorable impact on symptoms and/or survival. 12.6 CONSENT P ROCESS AND D OCUMENTATION The informed consent document will be provided as a physical or electronic document to the participant or consent designee as applicable, for review prior to consenting. A designated study investigator will carefully explain the procedures and tests involved in this study, and the associated risks, discomforts, and benefits. In order to minimize potential coercion, as much time as is needed to review the document will be given, including an opportunity to discuss it with friends, family members and/or other advisors, and to ask questions of any designated study investigator. A signed informed consent document will be obtained prior to entry onto the study. The initial consent process as well as re-consent, when required, may take place in person or remotely (e.g., via telephone or other site approved remote platforms used in compliance with policy, including HRPP Policy 303) per discretion of the designated study investigator and with the agreement of the participant/consent designee(s). Whether in person or remote, the privacy of the subject will be maintained. Consenting investigators (and participant/consent designee, when in person) will be located in a private area (e.g., clinic consult room). When consent is conducted remotely, the participant/consent designee will be informed of the private nature of the discussion and will be encouraged to relocate to a more private setting if needed. Note: When required, witness signature will be obtained similarly as described for the investigator and participant as described below. Consent will be documented with required signatures on the physical document (which includes the printout of an electronic document sent to participant. Signatures on electronic documents are described below. Note: FDA only regulates electronic signatures (i.e., an electronic timestamp is generated at the time of signature) in FDA regulated research. Manual (non-electronic) signature on electronic document: When a manual signature on an electronic document is used for the documentation of consent at the NIH Clinical Center, this study will use the Adobe platform (which is not 21 CFR Part 11 compliant) to obtain the required signatures. 90 Abbreviated Title: GBM Pembro HSPPC Version Date: 03/26/2024 During the consent process, participants and investigators will view individual copies of the approved consent document on screens at their respective locations. Both the investigator and the subject will sign the document using a finger, stylus or mouse. Electronic signature on electronic document: When permitted by the NIH Clinical Center, an electronic signature may be obtained using the iMedConsent platform to obtain the required signatures. During the consent process, participants and investigators will view individual copies of the approved consent document on screens at their respective locations. The identity of the participant will be determined by a prompt which will require the provision of information from a form of government-issued identification prior to obtaining the signature. If participant does not have such identification available, security questions will be used to confirm identity. Both the investigator and the subject will sign the document electronically per system prompts. For BTTC Participating multicenter sites : Each institution will follow their own local procedure for electronic signature requirements at participating site. 12.6.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation For NIH participants addressed in section 12.3, an LAR will be identified consistent with Policy 403 and informed consent obtained from the LAR, as described in Section 12.6. 12.6.2 Request for Waiver of Consent for Screening Activities Prior to the subject signing the consent for this study pre-screening activities listed in section 2.2.1 may be performed. We request a waiver of consent for these activities as they involve only minimal risk to the subjects. A waiver will not adversely affect the rights and welfare of the subjects given that the activities are only intended to determine suitability for screening for participation in research protocols. These activities could not practicably be carried out without the wavier as central recruiting services, utilized in the NIH Clinical Center, perform pre-screening activities for multiple studies and obtaining consent for each one is beyond their resources. The subjects will be provided with additional pertinent information after participation as they will be informed whether or not they are eligible to sign a consent for additional screening. 12.6.3 Reconsent via phone at BTTC Sites (outside of NCI) Each institution will follow their own procedure for reconsenting subjects. 91 Abbreviated Title: GBM Pembro HSPPC Version Date: 03/26/2024 13 REGULATORY AND OPERATIONAL CONSIDERATIONS 13.1 STUDY DISCONTINUATION AND CLOSURE This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. Written notification, documenting the reason for study suspension or termination, will be provided by the suspending or terminating party to study participants, site investigators, funding agency, the Investigational New Drug (IND) or Investigational Device Exemption (IDE) sponsor and regulatory authorities. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension. Study participants will be contacted, as applicable, and be informed of changes to study visit schedule. Circumstances that may warrant termination or suspension include, but are not limited to: Determination of unexpected, significant, or unacceptable risk to participants Demonstration of efficacy that would warrant stopping Insufficient compliance to protocol requirements Data that are not sufficiently complete and/or evaluable Determination that the primary endpoint has been met Determination of futility Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA). 13.2 QUALITY A SSURANCE AND QUALITY CONTROL Each clinical site will perform internal quality management of study conduct, data and biological specimen collection, documentation and completion. An individualized quality management plan will be developed to describe a site’s quality management. Quality control (QC) procedures will be implemented beginning with the data entry system and data QC checks that will be run on the database will be generated. Any missing data or data anomalies will be communicated to the site(s) for clarification/resolution. Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is conducted and data are generated and biological specimens are collected, documented (recorded), and reported in compliance with the protocol, International Council for Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). The investigational site will provide direct access to all trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities. 13.3 CONFLICT OF INTEREST P OLICY The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 92 Abbreviated Title: GBM Pembro HSPPC Version Date: 03/26/2024 required to have such conflicts managed in a way that is appropriate to their participation in the design and conduct of this trial. The study leadership in conjunction with the National Cancer Institute has established policies and procedures for all study group members to disclose all conflicts of interest and will establish a mechanism for the management of all reported dualities of interest. Participating sites will adhere to local conflict of interest policy guidelines. 13.4 CONFIDENTIALITY AND P RIVACY Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological samples and genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, documentation, data, and all other information generated will be held in strict confidence. No information concerning the study or the data will be released to any unauthorized third party without prior written approval of the sponsor. All research activities will be conducted in as private a setting as possible. The study monitor, other authorized representatives of the sponsor, representatives of the Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and records required to be maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site will permit access to such records. The study participant’s contact information will be securely stored at each clinical site for internal use during the study. At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be transmitted to and stored at the BTTC Coordinating Center. This will not include the participant’s contact or identifying information. Rather, individual participants and their research data will be identified by a unique study identification number. The study data entry and study management systems used by clinical sites and by BTTC Coordinating Center research staff will be secured and password protected. At the end of the study, all study databases will be archived at the BTTC Coordinating Center. To further protect the privacy of study participants, a Certificate of Confidentiality has been issued by the National Institutes of Health (NIH). This certificate protects identifiable research information from forced disclosure. It allows the investigator and others who have access to research records to refuse to disclose identifying information on research participation in any civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level. By protecting researchers and institutions from being compelled to disclose information that would identify research participants, Certificates of Confidentiality help achieve the research objectives and promote participation in studies by helping assure confidentiality and privacy to participants. 93 Abbreviated Title: GBM Pembro HSPPC Version Date: 03/26/2024 14 PHARMACEUTICAL INFORMATION 14.1 PEMBROLIZUMAB/K EYTRUDA ® 14.1.1 Chemical Name Humanized X PD-1_mAb (H409A11) IgG4 14.1.2 CAS Name and Number Anti-(human protein PDCD1 (programmed cell death 1)) immunoglobulin G4 (human-Mus musculus monoclonal heavy chain) disulfide with human-Mus musculus monoclonal light chain, dimer / 1374853-91-4 14.1.3 Molecular Formula: C 6534H10004N1716O2036S46 (peptide) 14.1.4 Molecular Weight: 149 kDa. 14.1.5 Appearance Sterile, preservative-free, white to off-white lyophilized powder in single-use vials.