Do not shake the vial. Pembrolizumab Solution for Infusion 100 mg/vial is a liquid DP (manufactured using the fully formulated DS), and has the identical formulation as that of the reconstituted lyophilized vial. 14.1.11 Preparation for Intravenous Infusion The liquid drug product is a clear to opalescent solution which may contain proteinaceous and extraneous particulates. Do not shake or freezer the vial(s). The liquid product is intended for IV administration. The liquid DP can be further diluted with 0.9% Sodium Chloride (normal saline) in IV containers made of polyvinyl chloride (PVC) or non-PVC material. The final concentration of the diluted solution should be between 1 mg/ml to 10 mg/ml. Do not dilute or combine product as an infusion with other medicinal products. Do not co-administer other drugs through the same infusion line. Administer infusion solution intravenously over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low- protein binding 0.2 micron to 5 micron in-line or add-on filter. The infusion solution should be immediately administered. If not used immediately, vials and/or IV bags may be stored at 2-8 °C for up to a cumulative time of 20 hours. If refrigerated, the vials and/or IV bags should be allowed to equilibrate to room temperature prior to subsequent use. Pembrolizumab solutions may be stored at room temperature for a cumulative time of up to 6 hours. This includes room temperature storage of reconstituted or liquid DP solution in vials, room temperature storage of infusion solution in the IV bag and the duration of infusion. 14.1.12 Incompatibilities No formal pharmacokinetic drug interaction studies have been conducted with Pembrolizumab. Live vaccines should be prohibited within 30 days prior to the first dose of trial treatment and while participating in the trial. 95 Abbreviated Title: GBM Pembro HSPPC Version Date: 03/26/2024 14.1.13 Side Effects 14.1.13.1 Non-Clinical Toxicology Summary of Results In the 1-month and 6-month toxicology study in cynomolgus monkeys, Pembrolizumab administered once a week and once every other week respectively, intravenously up to 200 mg/kg resulted in no adverse treatment related effects. The exposure multiple based on a predicted AUC 0-tau of 4464 μg.day/mL at the maximum anticipated human clinical dose of 10 mg/kg Q2W or Q3W is 15-fold at 200 mg/kg, the NOAEL for the 6-month monkey study. Additionally, in the tissue cross-reactivity study of Pembrolizumab with human and monkey tissues demonstrated the expected on-target staining of the membranes of mononuclear leukocytes in both species. Off-target cross-reactivity staining was also noted in both species but was limited to cytoplasm of various cell types/tissues and the stroma (extracellular connective tissue matrix), and was considered related to the experimental method artifacts, i.e. tissue processing for IHC, that are well recognized limitations of tissue cross-reactivity studies and, thus not considered toxicologically relevant. No reproductive or developmental toxicity studies are planned with Pembrolizumab. Therefore, inclusion of women of childbearing potential in clinical trials should be in accordance with the study protocol and applicable regulatory guidance (e.g., ICH M3(R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals). 14.1.13.2 Clinical Summary of Results As of 18-Oct-2013, 1,000 patients have been treated with Pembrolizumab at several dose schedules, including 10 mg/kg every 2 weeks. Pembrolizumab has been generally well tolerated, as expected based on preclinical findings and other anti-PD-1 monoclonal antibodies. As of 18- Oct-2013 no serious infusions reactions have been reported in PN001, however, since the potential exists in anti-PD-1 monoclonal antibodies, investigators should be vigilant to this possibility. Less than 1% of patients thus far assayed had confirmed positive ADA samples and among these, no or no clear impact on exposure has been observed. There is no contraindication to further clinical investigation with Pembrolizumab. Pharmacokinetics were as expected, based on Pembrolizumab being an IgG mAb and based on preclinical data, which support dosing once every 2 or 3 weeks. Pembrolizumab monotherapy induces an ORR of 25%/27% in patients with ipilimumab exposed melanoma by central independent RECIST and oncology review/investigator assessed irRC, respectively. Pembrolizumab monotherapy induces an ORR of 39%/43% in patients with ipilimumab-naive melanoma by central independent RECIST and oncology review/investigator assessed irRC, respectively. These responses are remarkably durable. The preliminary 1-year survival rate for patients, many of whom have had multiple therapies, including ipilimumab, who receive Pembrolizumab is 81%. Pembrolizumab monotherapy induces an ORR of 21%/24% in patients with previously-treated NSCLC by central independent RECIST/investigator assessed irRC, respectively, with these responses also remarkably durable. Preliminary data suggest higher levels of PD-L1 expression in tumors of NSCLC are associated with increased activity (ORR 67% by investigator assessed irRC/57% by central independent RECIST); additional data are required to define the optimal PD-L1 cut point. The most commonly reported treatment emergent AEs experienced are fatigue (43.8%), nausea (26.7%), cough (25.3%), pruritus (24.6%), diarrhoea (22.3%) and rash (21.5%). Immune-related adverse events were reported in 21.4% of melanoma patients; most of these events (15.8%) were considered drug-related by the 96 Abbreviated Title: GBM Pembro HSPPC Version Date: 03/26/2024 investigator. The most commonly reported, immune-related adverse events across the dose- schedules are rash (3.2%), pruritus (2.9%), vitiligo (2.9%), hypothyroidism (2.7%), arthralgia (2.2%), diarrhoea (2.2%), and pneumonitis (1.9%). Review of the overall benefit: risk ratio of Pembrolizumab favors enrollment of eligible patients into clinical trials of Pembrolizumab. The preliminary data suggest that a dose of Pembrolizumab at 2 mg/kg Q3W is appropriate for patients with melanoma. 14.1.13.3 Important Safety Considerations Based on results from the nonclinical studies, there are currently no specific safety considerations. Pembrolizumab is a humanized monoclonal Ab. Thus far, no serious infusion reactions have been reported however, patients should be closely monitored for potential AEs during antibody infusion and potential AEs throughout the study. In the event that a subject experiences an allergic reaction to Pembrolizumab, treatment (i.e., vasopressors, H2-blockers, antihistamines, H1-blockers, steroids) should be administered, as appropriate, and prophylaxis should be considered. Surveillance for the appearance of ADAs is included in all protocols. Pembrolizumab has the same mechanism of action as other anti-PD-1 monoclonal antibodies. Preclinical studies have suggested similar potency, and PK modeling has suggested similar human PK in the class. Accordingly, the AEs observed with other anti-PD-1 antibodies may serve as in indicator for the AEs to expect for Pembrolizumab in cancer patients. Furthermore, AEs from other immunotherapies for cancer were considered in the Events of Clinical Interest (Section ) and Immune-Related Guidance. 14.1.13.4 Immune-Related Adverse Events (I-R AE) An I-R-AE is defined as a clinically significant AE of any organ that is associated with study drug exposure, is of unknown etiology, and is consistent with an immune-related mechanism. Immune-related adverse events were reported in 21.4% of melanoma patients; most of these events (15.8%) were considered drug- related by the investigator. The most commonly reported, immune-related adverse events across the dose-schedules are rash (3.2%), pruritus (2.9%), vitiligo (2.9%), hypothyroidism (2.7%), arthralgia (2.2%), diarrhoea (2.2%), and pneumonitis (1.9%). The organ most frequently affected by irAEs with Pembrolizumab is the skin. Less frequently affected tissues include thyroid gland, colon, lung, kidney, and liver. Based on the mechanism of action of Pembrolizumab and similar immunomodulatory agents, the sponsor is keenly interested in potential events of colitis, hepatitis, hyper/hypothyroidism, nephritis, pneumonitis. Therefore, the sponsor encourages appropriate academic investigation of signs and symptoms suggestive of any of the above events. Consultation with the appropriate medical specialist should be considered when investigating a possible irAE. These events can occur after the first dose to several months after the last dose of treatment. Mild irAEs are usually treated symptomatically and do not require dosing delays or discontinuation. Higher grade and persistent lower grade irAEs typically necessitate withholding or discontinuing treatment and administration of systemic steroids or other immunosuppressive agents (such as tumor necrosis factor blockers), when systemic steroids are not effective. Early recognition of irAEs and initiation of treatment are critical to reduce the risk of complications, since the majority of irAEs are reversible with the use of steroids and other immune suppressants. 97 Abbreviated Title: GBM Pembro HSPPC Version Date: 03/26/2024 14.1.13.4.1 Other immune-mediated adverse reactions The following additional clinically significant, immune-mediated adverse reactions were reported in less than 1% of patients treated with KEYTRUDA (pembrolizumab) in KEYNOTE-001, KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010: uveitis, myositis, Guillain- Barré syndrome, pancreatitis, encephalitis, sarcoidosis, myasthenic syndrome/myasthenia gravis (including exacerbation) and), myelitis., and vasculitis. The following were reported in other clinical studies with KEYTRUDA or in postmarketing use: myocarditis and sclerosing cholangitis. Cases of these immune-mediated adverse reactions, some of which were severe, have been reported in clinical trials or in postmarketing use. 14.1.13.5 Nursing Implications Standard treatment protocols per hospital guidelines will be used for this Pembrolizumab. Dose will be administered prior to RT. 14.2 TEMOZOLOMIDE Temozolomide during Concomitant Radiation Therapy (RT) TMZ will be administered orally on day 1 of radiation therapy (RT) 1-2 hours before each session of radiotherapy or night before RT; and it should be administered the same time throughout the course of RT. TMZ should continue throughout RT at the dose of 75 mg/m2/day. During weekends without radiotherapy (Saturday and Sunday), the drug will be taken at the same time as radiotherapy days. 14.2.1 Chemical Name Temozolomide is 3,4-dihydro-3methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide 14.2.2 Molecular Formula: C 6H6N6O2 14.2.3 Molecular Weight: 194.15 14.2.4 Appearance white to light tan/light pink powder 14.2.5 Supply: Commercially Available. 14.2.6 Pill Diary Temozolomide will be properly accounted for, handled, and disposed in accordance with existing federal regulations and principles of Good Clinical Practice. All oral study drugs will be recorded in the patient diaries found in Appendix 16.14. This will be used as a memory aide for subjects.