Minimal information includes demography, screen failure details, eligibility criteria, and any serious adverse event (SAE). 34 Abbreviated Title: GBM Pembro HSPPC Version Date: 03/26/2024 2.4 TREATMENT A SSIGNMENT AND RANDOMIZATION /STRATIFICATION PROCEDURES Cohorts Number Name Description 1 Patients with Glioblastoma eligible to receive radiation therapy GBM patients with MRI findings consistent with a suspected GBM or a histologically confirmed newly diagnosed GBM that has not been treated, have met all inclusion and no exclusion criteria, and have completed surgery (i.e., Step 2 of registration) 2 Patients with Glioblastoma with sufficient vaccine createdGBM patients with MRI findings consistent with a suspected GBM or a histologically confirmed newly diagnosed GBM that has not been treated, whose tumors have an unmethylated MGMT promoter and are IDH wildtype with sufficient vaccine created (i.e., Step 3 of registration) 3 Patients with Glioblastoma without sufficient vaccine createdGBM patients with MRI findings consistent with a suspected GBM or a histologically confirmed newly diagnosed GBM that has not been treated, whose tumors have an unmethylated MGMT promoter and are IDH wildtype without sufficient vaccine created (i.e., Step 3 of registration) Arms Number Name Description 1 Radiation Therapy (RT) Standard radiation therapy 2 RT+TMZ + Pembrolizumab Standard treatment with experimental treatment (pembro) added 3 RT+TMZ+Pembrolizumab+HSPPC-96 VaccineStandard treatment with experimental treatment (pembro+ vaccine) added 4 RT+TMZ+Pembrolizumab+Placebo VaccineStandard treatment with experimental treatment and placebo added Randomization and Arm Assignment All study patients satisfying the eligibility criteria and who have completed surgery will be assigned to Cohort 1 and Arm 1, Radiation Therapy. All study patients that satisfy the eligibility criteria post-radiation therapy, will be assigned to Cohort 2 or 3, based on ability or inability to make sufficient vaccine. Study patients in Cohort 2 will then be randomized 1:1 in a blinded fashion between arms 3 and 4. Patients in cohort 3 will be assigned directly to the ancillary arm, Arm 2. 35 Abbreviated Title: GBM Pembro HSPPC Version Date: 03/26/2024 Stratifications Name Distinct Options Notes None 3 STUDY IMPLEMENTATION 3.1 EARLY TERMMINATION On May 20, 2021 the NCI/CCR Data Safety and Monitoring Board met to review the progress of this protocol, including the results of an unscheduled interim analysis. Prior to the meeting, the board agreed to a request by the Lead NCI PI to look at outcome data by arm and agreed on principles for interpretation of outcome and accrual data. Based on the presented data, the board recommended the study be stopped because of poor accrual. The board deferred to the principal investigator on how to enact an orderly termination of the study including continued treatment and unblinding of patients. Because this is a multi-institutional trial, the IRBs of all institutions participating in this study must be informed by the Lead NCI PI about this DSMB’s decision. Sections throughout the protocol have been revised to reflect that the study is closed to new enrollment and to describe the early termination procedures. The revisions include decisions for how long participants currently enrolled will remain on study after the unblinding. Below are guidelines for unblinding and follow up per Study Arm: Ancillary Arm 2: For participants assigned to RT+TMZ + Pembrolizumab, they will remain on treatment and will be followed for overall survival per Study Calendar. Arm 3: For participants randomized to the RT+TMZ+Pembrolizumab+HSPPC-96 Vaccine, they will be unblinded but may remain on treatment to receive TMZ, Pembro and/or HSPPC-96 vaccine and will be followed for overall survival per Study Calendar. Arm 4: For participants randomized to RT+TMZ+Pembrolizumab+Placebo Vaccine, they will be unblinded but may remain on treatment to receive TMZ and/or Pembro and will be followed for overall survival per Study Calendar. Placebo vaccine will be discontinued as permitted per Section 3.10. Participants who decide to discontinue treatment will continue to be followed for overall survival. 3.2 STUDY DESIGN This will be a randomized, double blind phase II trial of surgery, RT + TMZ + Pembrolizumab followed by TMZ + Pembrolizumab with HSPPC-96 vaccine or placebo vaccine in newly diagnosed GBM patients whose tumor has an unmethylated MGMT promoter and is IDH wildtype. 36 Abbreviated Title: GBM Pembro HSPPC Version Date: 03/26/2024 Subjects will be randomized without stratification on a 1:1 basis, using variable block sizes. The first block will be of size n=6 in order to facilitate the evaluation of toxicity and safety in the first 3 patients on each arm. The study will utilize the Recommended Phase 2 Dose (RP2D) for RT + TMZ + Pembrolizumab which was TMZ 75 mg/m2, RT approximately 60Gy and Pembrolizumab 200 mg every 3 weeks. HSPPC-96 is not expected to result in additional toxicity although the first 3 subjects treated in each arm will be observed for toxicity before further enrollment. The primary endpoint is: oTo determine whether the one-year overall survival rate (OS) is improved in newly diagnosed GBM patients whose tumor is MGMT promoter unmethylated and is IDH wildtype treated with RT + TMZ + Pembrolizumab followed by Pembrolizumab + TMZ + HSPPC-96 vaccine (or placebo vaccine) x 6 cycles (1 cycle is 9 weeks). Nota Bene: Those patients whose tumor does not meet the criteria (unmethylated MGMT promoter and IDH wildtype by pathology) and with < 80% of contrast enhanced tumor or < 7grams of tumor resected are ineligible. All eligible patients will be treated with standard RT to approximately 60 Gy (180 cGy (1.8 Gy) x 33 or 200 cGy (2.0 Gy) x 30). Initial dose of TMZ during radiation will be 75 mg/m2/day 7 days per week and Pembrolizumab 200 mg every 3 weeks. 3.2.1 Blinding This study will utilize a placebo control for the vaccine in order to fulfill the double blind design of the study.