Pembrolizumab and Radiation Therapy with or without Bevacizumab in Treating Patients with Recurrent Glioblastoma

Inclusion Criteria

• Have histologically confirmed World Health Organization (WHO) grade IV glioblastoma. Participants will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of glioblastoma is made. Other WHO grade IV glial neoplasms such as gliosarcoma are NOT eligible
• Be willing and able to provide written informed consent/assent for the trial
• Have a Karnofsky performance status (KPS) >= 70
• Participants must have shown unequivocal evidence for tumor progression by magnetic resonance imaging (MRI) scan
• MRI within 14 days prior to start of study therapy. 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 scan and the start of treatment, a new baseline MRI or computed tomography (CT) is required
• Measurable disease as per RANO criteria
• Be at first or second relapse (cohort A). For cohort B, participants must have progressed on no more than one prior bevacizumab-containing regimen (cohort B). Participants who were treated with prior bevacizumab but did not progress or experienced significant toxicity, are not eligible * 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 beyond surgery for a low-grade glioma that is considered standard of care for high-grade glioma (radiation therapy, chemotherapy with temozolomide or nitrosoureas, etc), the surgical diagnosis of glioblastoma will be considered the first relapse ** Patients in screening for Cohort B may have received any # of non-bevacizumab-containing regimens
• Previous first line therapy with at least radiotherapy utilizing standard dosing of central nervous system (CNS) radiation for either high-grade or low-grade glial neoplasm
• From the projected start of scheduled study treatment, the following time periods must have elapsed: * At least 3 weeks from prior surgical resection ** Participants having undergone recent resection of recurrent or progressive tumor will be eligible as long as they have recovered from the effects of surgery and have measurable residual disease prior to starting study therapy * At least 1 week from stereotactic biopsy * At least 6 months from completion of prior radiotherapy ** If patients have not passed an interval of at least 6 months, they may still be eligible if they meet the following criteria: *** New area of enhancement outside the 80% isodose line of the original radiation field as determined by the treating investigator * At least 4 weeks (or 5 half-lives, whichever is shorter) from any investigational agent * At least 4 weeks from cytotoxic therapy ** Exceptions: *** At least 23 days for temozolomide *** At least 6 weeks from nitrosoureas ** At least 4 weeks (or 5 half-lives, whichever is shorter) for daily administered chemotherapeutics * 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 (or biosimilar) on-study must be at least 3 weeks from last dose of prior course of Avastin/bevacizumab
• Participants must have recovered to grade 0 or 1 or pre-treatment baseline from clinically significant toxic effects of prior therapy (exceptions include alopecia, laboratory values listed per inclusion criteria, and lymphopenia, which is common after therapy with temozolomide)
• Absolute neutrophil count (ANC) >= 1,500 /mcL (performed within 14 days of treatment initiation)
• Platelets >= 100,000 / mcL (performed within 14 days of treatment initiation)
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (performed within 14 days of treatment initiation) * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
• 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 creatinine clearance [CrCl]) >= 60 mL/min for participant with creatinine levels > 1.5 x institutional ULN (performed within 14 days of treatment initiation) * Creatinine clearance (CrCl) should be calculated per institutional standard
• Serum total bilirubin =< 1.5 X institutional ULN OR direct bilirubin =< institutional ULN for participants with total bilirubin levels > 1.5 X institutional ULN (performed within 14 days of treatment initiation)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X institutional ULN OR =< 5 X institutional ULN for participants with Gilberts syndrome (performed within 14 days of treatment initiation)
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X institutional ULN unless participant is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants (performed within 14 days of treatment initiation)
• 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 (performed within 14 days of treatment initiation)
• Resting baseline oxygen saturation by pulse oximetry >= 92% at rest (performed within 14 days of treatment initiation)
• Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must have a negative urine or serum pregnancy within 72 hours prior to registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * Women in the following categories are not considered WOCBP: ** Premenarchal ** Premenopausal female with 1 of the following: *** Documented hysterectomy *** Documented bilateral salpingectomy *** Documented bilateral oophorectomy **** Note: documentation can come from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview ** Postmenopausal female *** A postmenopausal state is defined as no menses for 12 months without an alternative medical cause **** A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with two FSH measurements in the postmenopausal range is required *** Females on HRT and whose menopausal status is in doubt will be required to use one of the non-hormonal highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment
• Women of child-bearing potential (WOCBP), must agree to use a highly effective method of contraception consistently and correctly as described below during study treatment and for 120 days after study discontinuation * Highly effective contraceptive methods that are user dependent (failure rate of < 1% per year when used consistently and correctly) ** Combined (estrogen- and progestogen-containing) hormonal contraception *** Oral *** Intravaginal *** Transdermal *** Injectable ** Progestogen-only hormonal contraception *** Oral *** Injectable * Highly effective methods that have low user dependency (failure rate of < 1% per year when used consistently and correctly) ** Progestogen-only contraceptive implant ** Intrauterine hormone-releasing system (IUS) ** Intrauterine device (IUD) ** Bilateral tubal occlusion ** Vasectomized partner *** A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used ** Sexual abstinence *** Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant * NOTES: use should be consistent with local regulations regarding the use of contraceptive methods for participants of clinical studies ** Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and correctly) ** If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, condoms must be used in addition to the hormonal contraception during the treatment period and for at least during study treatment and for 120 days after study discontinuation after the last dose of study treatment ** If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive implants are limited to those which inhibit ovulation
• Male participants must agree to use at least one of the following methods of contraception starting with the first dose of study therapy through 120 days after the last dose of therapy: * Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent * Use a male condom plus partner use of a contraceptive method with a failure rate of < 1% per year when having penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant ** Note: men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile penetration

Exclusion Criteria

• Has recurrent tumor greater than 6 cm in maximum diameter
• Is currently participating or plans to participate in another study of an investigational agent or using an investigational device * Note: participants who have entered the follow-up phase of an investigational study may participate as long as it has been at least 4 weeks (or 5 half-lives, whichever is shorter) from the last dose of the previous investigational agent to date of registration
• Has tumor primarily localized to the brainstem or spinal cord
• Has 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)
• Has a diagnosis of immunodeficiency
• Has a 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. Examples include - but are not limited to - unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements
• 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 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)
• Has active autoimmune disease requiring systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement for adrenal insufficiency or pituitary/hypothalamic dysfunction, etc.) is not considered a form of systemic treatment
• Has history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
• Has an active infection requiring systemic therapy
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) and is receiving antiretroviral therapy. Such patients are ineligible because of the potential for pharmacokinetic interactions with pembrolizumab and because these participants are at increased risk of lethal infections. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated
• 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 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 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 known history of active TB (Bacillus tuberculosis)
• Has a known hypersensitivity to any of the study therapy products and/or any of their excipients
• 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. Pregnant women are excluded because there is an unknown but potential risk for adverse events affecting a developing fetus and/or the mother secondary to treatment with pembrolizumab. There is also an unknown but potential risk for adverse events affecting nursing infants secondary to treatment of the mother with pembrolizumab, thus, breastfeeding must be discontinued if the mother is treated with pembrolizumab
• 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)
• 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 (e.g. CTLA-4, OX-40, CD137)
• Has received prior VEGF or VEGFR inhibitor therapy such as bevacizumab, cediranib, aflibercept, vandetanib, XL-184, sunitinib, etc. (Cohort A only)
• 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
• Has received systemic immunosuppressive treatments, aside from systemic corticosteroids (such as methotrexate, chloroquine, azathioprine, etc), within six months of start of study drug
• 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 (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
• 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 received a live vaccine within 30 days prior to the first dose of study drug * Examples of live vaccines include - but are not limited to - the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed