Pembrolizumab and Reirradiation in Bevacizumab Naïve and Bevacizumab Resistant Recurrent Glioblastoma

Exclusion Criteria

• •1. At least 3 weeks from prior surgical resection
• •2. At least 1 week from stereotactic biopsy
• •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.