Pembrolizumab with or without Bevacizumab in Treating Patients with Recurrent Glioblastoma Who Have Not Previously Received Bevacizumab

Inclusion Criteria

• Have histologically confirmed World Health Organization grade IV malignant glioma (glioblastoma or gliosarcoma); participants will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of glioblastoma or variants is made
• Be willing and able to provide written informed consent/assent for the trial
• Have a Karnofsky performance status (KPS) >= 70
• Previous first line therapy with at least radiotherapy and temozolomide
• Be at first or second relapse; Note: relapse is defined as progression following initial therapy (i.e., radiation +/- chemotherapy); if the participant had a surgical resection for relapsed disease and no antitumor therapy was instituted for up to 12 weeks, this is considered one relapse; for participants who had prior therapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma will be considered the first relapse
• Participants must have shown unequivocal evidence for tumor progression by magnetic resonance imaging (MRI) or computed tomography (CT) scan
• Within 14 days of treatment initiation: Absolute neutrophil count (ANC) >= 1,500 /mcL
• Within 14 days of treatment initiation: Platelets >= 100,000/mcL
• Within 14 days of treatment initiation: Hemoglobin >= 9 g/dL or >= 5.6 mmol/L
• Within 14 days of treatment initiation: Serum creatinine =< 1.5 X institutional upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or CrCl) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN * Creatinine clearance should be calculated per institutional standard
• Within 14 days of treatment initiation: Serum total bilirubin =< 1.5 X institutional ULN OR direct bilirubin =< institutional ULN for subjects with total bilirubin levels > 1.5 institutional ULN
• Within 14 days of treatment initiation: Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional ULN OR =< 5 X institutional ULN for subjects with Gilberts syndrome
• Within 14 days of treatment initiation: International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X institutional ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
• Within 14 days of treatment initiation: Activated partial thromboplastin time (aPTT) =< 1.5 X institutional ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
• CT or MRI within 14 days prior to start of study drug; MRIs should include 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 or CT scan and the start of treatment, a new baseline MRI or CT is required
• An interval of at least 4 weeks (to start of study agent) between prior surgical resection or one week for stereotactic biopsy
• An interval of at least 12 weeks from the completion of radiation therapy to start of study drug unless there is a new area of enhancement consistent with recurrent tumor outside the radiation field or there is unequivocal histologic confirmation of tumor progression
• Participants must have recovered to grade 0 or 1 or pre-treatment baseline from clinically significant toxic effects of prior therapy (including but not limited to exceptions of alopecia, laboratory values listed per inclusion criteria, and lymphopenia which is common after therapy with temozolomide)
• From the projected start of scheduled study treatment, the following time periods must have elapsed: 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies
• Participants having undergone recent resection of recurrent or progressive tumor will be eligible as long as the following conditions apply: * They have recovered from the effects of surgery * Residual disease following resection of recurrent tumor is not mandated for eligibility; to best assess the extent of residual disease post-operatively, an MRI or CT scan should be done no later than 96 hours following surgery or at least 4 weeks post-operatively, in either case within 14 days prior to start of study drug; if the participant is taking corticosteroids, the 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 or CT scan and the start of treatment, a new baseline MRI or CT is required
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required; women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels > 40 mIU/mL and estradiol < 20 pg/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential
• Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during study treatment and for 120 days after study discontinuation; highly effective contraception is defined as either: * True abstinence: when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception * Sterilization: surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment (as described above) * Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); for female subjects on the study, the vasectomized male partner should be the sole partner for that participant * Use of a combination of any two of the following: ** Placement of an intrauterine device (IUD) or intrauterine system (IUS) ** Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository ** Appropriate hormonal contraceptives (including any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent - including oral, subcutaneous, intrauterine, or intramuscular agents)
• Male subjects should agree to use adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of therapy

Exclusion Criteria

• Current or planned participation in a study of an investigational agent or using an investigational device
• Has a diagnosis of immunodeficiency
• Has tumor primarily localized to the brainstem or spinal cord
• Has presence of diffuse leptomeningeal disease or extracranial disease
• Has received systemic immunosuppressive treatments, aside from systemic corticosteroids as described below (such as methotrexate, chloroquine, azathioprine, etc) within six months of start of study drug
• Requires treatment with high dose systemic corticosteroids defined as dexamethasone > 4 mg/day or bioequivalent for at least 3 consecutive days within 2 weeks of start of study drug
• Has received prior interstitial brachytherapy, implanted chemotherapy, stereotactic radiosurgery or therapeutics delivered by local injection or convection enhanced delivery
• 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; however, therapeutic or prophylactic therapy with low-molecular weight heparin is allowed
• Has history of known coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhage within 12 months of start of study drug
• Has 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
• Has gastrointestinal bleeding or any other hemorrhage/bleeding event Common Terminology Criteria for Adverse Events (CTCAE) grade > 3 within 6 months of start of study drug
• Has a known additional malignancy that is progressing or requires active treatment within 3 years of start of study drug; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
• Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo, type 1 diabetes mellitus, residual hypothyroidism due to autoimmune condition requiring hormone replacement, psoriasis not requiring systemic treatment, conditions not expected to recur in the absence of an external trigger or resolved childhood asthma/atopy would be exceptions to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjogren’s syndrome will not be excluded from the study
• Has evidence of interstitial lung disease or active, non-infectious pneumonitis
• Has an active infection requiring systemic therapy
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator; examples include but are not limited to symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• 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
• Has received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1, anti-PD-L2, anti-cluster of differentiation (CD)137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Has received a live vaccine within 30 days prior to the first dose of study drug
• Has a known hypersensitivity to any of the study therapy products
• Has received anti-angiogenic or anti-vascular endothelial growth factor (VEGF) targeted agents (e.g. bevacizumab, cediranib, aflibercept, vandetanib, XL-184, sunitinib, etc.)
• Has greater than 1+ proteinuria on a urine dipstick or equivalent routine laboratory analysis will require further testing with a urine protein to creatinine ratio (UPCR); if the UPCR >= 1, then the patient will not be eligible for study entry; however, if urinalysis or equivalent routine laboratory analysis shows no protein, then UPCR testing is not required
• Has a history of non-healing wounds or ulcers, or bone refractures within 3 months of fracture
• Has a history of arterial thromboembolism within 12 months of start of study drug
• Has inadequately controlled hypertension (defined as systolic blood pressure greater than 150 mm Hg or diastolic blood pressure greater than 95 mm Hg); the use of antihypertensive medications to control blood pressure is permitted
• Has a history of hypertensive crisis or hypertensive encephalopathy
• Has had 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
• Has a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to start of study drug