This research study is studying pembrolizumab and re-irradiation as possible treatments for glioblastoma.

The drugs involved in this study are:

• Pembrolizumab
• Radiation
• Bevacizumab, an FDA-approved drug for treating recurrent glioblastoma multiforme (GBM)

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

How the Study Interventions work:

Pembrolizumab: Pembrolizumab has been studied in lab experiments and in other types of cancer, and information from these studies suggests that it may be beneficial in this type of cancer. Pembrolizumab is a drug (an antibody) that may treat cancer by working with the immune system.

The FDA (the U.S. Food and Drug Administration) has not approved pembrolizumab for this specific disease but it has been approved for other uses.

Radiation (Re-irradiation): Radiotherapy destroys cancer cells using radiation aimed at a cancer from a machine.

The FDA (the U.S. Food and Drug Administration) has approved re-irradiation as a treatment option for this disease.

Bevacizumab: Bevacizumab (also known as "Avastin") is designed to prevent or slow down the growth of cancer cells by blocking the growth of blood vessels.

The FDA (the U.S. Food and Drug Administration) has approved bevacizumab as a treatment option for this disease.

In this research study, the investigators are looking to determine if this combination (pembrolizumab + re-irradiation) proves helpful in treating this cancer. If the participant has already been receiving bevacizumab, the participant will continue to receive this along with pembrolizumab and re-irradiation. By doing this, the investigators will look to determine if this combination (pembrolizumab and bevacizumab + re-irradiation) proves helpful in treating this cancer.

This study will also test the safety and tolerability of this combination (pembrolizumab + re-irradiation) when given alone or with bevacizumab

INCLUSION CRITERIA:

1.1 Histologically confirmed World Health Organization (WHO) Grade IV glioblastoma. Patients with original histology of low-grade glioma and subsequent histological diagnosis of GBM are eligible. Other WHO grade IV glial neoplasms such as gliosarcoma are NOT eligible 1.2 Willing and able to provide written informed consent/assent for the trial 1.3 ≥ 18 years of age on day of signing informed consent 1.4 Karnofsky performance status (KPS) ≥ 70 (Appendix A) 1.5 Unequivocal evidence for tumor progression by MRI scan 1.6 MRI within 14 days prior to start of study therapy (with vascular imaging when possible). Corticosteroid dose must be stable or decreasing for at least 5 days prior to the scan. If steroids are added or the steroid dose is increased between the date of the screening MRI scan and Day 1 dose, a new baseline scan is required 1.7 Measurable disease as per Response Assessment in Neuro-Oncology (RANO) criteria 1.8 Cohort A patients must be at their first or second relapse; Cohort B patients must have progressed on no more than one prior bevacizumab-containing regimen (may have received any # of non-bevacizumab-containing regimens). Patients who were treated with prior bevacizumab but did not progress or experienced significant toxicity, are not eligible 1.9 Previous first line therapy with at least radiotherapy utilizing standard dosing of CNS radiation - for either high-grade or low-grade glial neoplasm 1.10 The following time periods must have elapsed from projected Day 1 dose:

1. At least 3 weeks from prior surgical resection
2. At least 1 week from stereotactic biopsy
3. At least 6 months from completion of prior radiotherapy (patient may still be eligible if s/he has a new area of enhancement outside the 80% isodose line of the original radiation field)
4. At least 4 weeks from cytotoxic therapy (at least 23 days for temozolomide, and at least 6 weeks from nitrosoureas)
5. At least 1 week from cancer vaccines
6. At least 6 weeks from antibodies
7. At least 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies (not including tumor treating fields or cancer vaccines); at least 1 week from NovoTTF (Optune) or other tumor treating fields and cancer vaccines
8. Cohort B patients only: Day 1 of bevacizumab on-study must be at least 3 weeks from last dose of prior course of Avastin/bevacizumab.

1.11 All clinically significant toxic effects of prior therapy must have recovered to grade 0 or 1 or pre-treatment baseline (excluding alopecia, laboratory values listed per inclusion criteria, and lymphopenia) 1.12 Adequate organ function as defined below (screening labs performed within 14 days of treatment initiation): 1.12.1 Hematologic: Absolute neutrophil count (ANC) ≥1,500 /uL; Platelets ≥100,000 / uL; Hemoglobin ≥9 g/dL or ≥5.6 mmol/L 1.12.2 Renal: Serum creatinine ≤1.5 X institutional upper limit of normal (ULN) OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥60 mL/min for participant with creatinine levels > 1.5 X institutional ULN 1.12.3 Hepatic Serum total bilirubin ≤ 1.5 X institutional ULN OR Direct bilirubin ≤ institutional ULN for participants with total bilirubin levels > 1.5 X institutional ULN; aspartate aminotransferase (AST; SGOT) and alanine aminotransferase (ALT; SGPT) ≤ 2.5 X institutional ULN (OR ≤ 5 X institutional ULN for participants with Gilberts syndrome) 1.12.4 Coagulation: International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) ≤1.5 X institutional ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants 1.12.5 Pulmonary: Resting baseline oxygen saturation by pulse oximetry ≥92% at rest

1.13 Negative urine or serum pregnancy within 72 hours prior to registration from any woman of child-bearing potential (WOCBP), defined as any woman physiologically capable of becoming pregnant. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

1.14 WOCBP (defined above) must agree to use a highly effective method of contraception (detailed in protocol eligibility) consistently and correctly as described below during study treatment and for 120 days after study discontinuation.

1.15 Male participants must agree to use at least one of the methods of contraception detailed in protocol eligibility starting with the first dose of study therapy through 120 days after the last dose of therapy.

EXCLUSION CRITERIA:

2.1 Recurrent tumor greater than 6 cm in maximum diameter 2.2 Currently participating or plans to participate in another study of an investigational agent or using an investigational device.

2.3 Tumor primarily localized to the brainstem or spinal cord. 2.4 Presence of multifocal tumor, diffuse leptomeningeal or extracranial disease.

NOTE: Not all instances of multifocal disease will exclude a potential patient; only patients with multifocal sites of active disease will be excluded. (e.g. A patient with a previously treated lesion that remains stable would not be excluded.)

Medical History/Conditions/Concomitant Medical Illnesses:

2.5 Diagnosis of immunodeficiency. 2.6 History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. e.g. unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements.

2.7 History of known coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhage within 12 months of start of study drug.

2.8 Evidence of intratumoral or peritumoral hemorrhage on baseline MRI scan other than those that are grade ≤ 1 and either post-operative or stable on at least 2 consecutive MRI scans.

2.9 Gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE Grade > 3 within 6 months of start of study drug.

2.10 Known additional malignancy that is progressing or requires active treatment within 1 year of start of study drug, except for those treated with surgical therapy only (e.g. basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy).

2.11 Active autoimmune disease requiring systemic treatment in the past 2 years (e.g. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg thyroxine, insulin, or physiologic corticosteroid replacement for adrenal insufficiency or pituitary/hypothalamic dysfunction, etc.) is not considered a form of systemic treatment.

2.12 History of (non-infectious) pneumonitis that required steroids or has current pneumonitis.

2.13 Active infection requiring systemic therapy. 2.14 Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

2.15 Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) and is receiving antiretroviral therapy.

2.16 Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C [e.g., hepatitis C virus (HCV) RNA (qualitative) is detected].

2.17 History of non-healing wounds or ulcers, or bone refractures within 3 months of fracture.

2.18 History of arterial thromboembolism within 12 months of start of study drug.

2.19 Clinically significant cardiovascular disease within 12 months of start of study drug, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication, percutaneous transluminal coronary angioplasty/stent.

2.20 Known history of active Bacillus Tuberculosis (TB) 2.21 Known hypersensitivity to any of the study therapy products and/or any of their excipients.

2.22 Is pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.

Prior Therapy:

2.23 Has received prior interstitial brachytherapy, implanted chemotherapy, stereotactic radiosurgery or therapeutics delivered by local injection or convection enhanced delivery (this exclusion applies to any locally administered therapy, including intratumoral vaccines).

2.24 Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 or with an agent directed to another stimulatory or co-stimulatory T-cell receptor (eg CTLA-4, OX-40, CD137). (These therapies target checkpoint proteins on immune cells called T-Cells.PD-1 = Programmed cell death protein 1. CTLA-4 = cytotoxic T-lymphocyte-associated protein 4. OX-40 - AKA CD134 & TNFRSF4 = Tumor necrosis factor receptor superfamily, member 4) 2.25 Has received prior Vascular endothelial growth factor (VEGF) or VEGFR inhibitor therapy such as bevacizumab, cediranib, aflibercept, vandetanib, XL-184 (Cabozantinib), sunitinib, etc. (Cohort A only)

Other Meds:

2.26 Is receiving any form of immunosuppressive therapy (e.g. chronic systemic steroid therapy exceeding dosage of 10 mg daily of prednisone equivalent) within 7 days prior to the first dose of study drug.

2.27 Has received systemic immunosuppressive treatments (aside from systemic corticosteroids as described in protocol) within six months of start of study drug (such as methotrexate, chloroquine, azathioprine, etc).

2.28 Requires treatment with high dose systemic corticosteroids defined as dexamethasone > 2 mg/day or bioequivalent for at least 3 consecutive days within 2 weeks of start of study drug.

• Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Participants are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption).
• Physiologic replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents.
• A brief course of corticosteroids for prophylaxis or for treatment of non-autoimmune conditions is permitted.

2.29 Requires therapeutic anticoagulation with warfarin at baseline; patients must be off warfarin or warfarin-derivative anti-coagulants for at least 7 days prior to starting study drug. (Therapeutic or prophylactic therapy with low-molecular weight heparin is allowed.) 2.30 Has received a live vaccine within 30 days prior to the first dose of study drug.

Populations are defined by treatment assignment; Safety Lead-in and Phase II patient information is reported together

Adverse Events (AEs) were collected from registration through 30 days after last dose. Serious AEs (SAEs) were collected through 90 days after last dose (or 30 days if pt initiated new anticancer therapy). AEs were followed for a max of 2 years on this trial. Participants were followed every 3 months (+/- 1 month) until death for survival. Survival was followed for a max of 4 years on this trial.

An AE is any undesirable sign, symptom or medical condition that develops or worsens in severity after initiating study treatment or any protocol-specified procedure, regardless of attribution. An SAE is any AE at any dose & regardless of causality that: results in death, is life-threatening, requires or prolongs inpatient hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly or birth defect, or is an important medical event