Pembrolizumab and Reirradiation in Bevacizumab Naïve and Bevacizumab Resistant Recurrent Glioblastoma

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:

• At least 3 weeks from prior surgical resection
• At least 1 week from stereotactic biopsy
• 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)
• At least 4 weeks from cytotoxic therapy (at least 23 days for temozolomide, and at least 6 weeks from nitrosoureas)
• At least 1 week from cancer vaccines
• At least 6 weeks from antibodies
• 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
• 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 beco