Pembrolizumab and Stereotactic Radiation for the Treatment of Patients with Recurrent Glioblastoma

Inclusion Criteria

• Age 18 years or older
• Confirmed histologic diagnosis of World Health Organization (WHO) Grade IV, glioblastoma multiforme
• Glioblastoma multiforme (GBM) recurrence or progression on imaging that is amenable to standard of care surgical resection and repeat radiation
• Tumor size less than 6 cm
• Eastern Cooperative Oncology Group performance status (ECOG) of 0 or 1 OR Karnofsky Performance Score (KPS) of >= 70%
• White blood cells (WBCs) >= 2.00 x 1000/uL
• Absolute neutrophil count (ANC) >= 1.5 x 1000/uL
• Platelets >= 100 x 1000/ul
• Hemoglobin >= 9.0 g/dL
• Serum creatinine =< 2 mg/dL (or glomerular filtration rate >= 40 ml/min)
• Aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN)
• Alanine aminotransferase (ALT) =< 2.5 x ULN
• Bilirubin within institutional normal limits for age (except subjects with Gilbert’s syndrome, who must have total bilirubin < 3.0 mg/dL)
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN
• Men with partners of childbearing potential must use an acceptable method of contraception to avoid pregnancy throughout the study and for at least 4 months after the last dose of study agents. Acceptable contraceptive methods for men: * Sexual abstinence of vaginal intercourse * Male condom plus partner use of an acceptable method of contraception when having vaginal intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant ** Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from vaginal intercourse or use a male condom during vaginal intercourse
• Women of childbearing potential (WOCBP) must be using an acceptable method of contraception to avoid pregnancy throughout the study and for at least 4 months after the last dose of pembrolizumab in such a manner that the risk of pregnancy is minimized. See below for the definition of WOCBP and acceptable contraceptive methods Women of childbearing potential include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Post menopause is defined as: * Amenorrhea >= 12 consecutive months without another cause and a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL * Women with irregular menstrual periods and a documented FSH level > 35 mIU/mL * Women on hormone replacement therapy (HRT) Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential Acceptable contraceptive methods for WOCBP: * Hormonal contraceptives (oral, vaginal products, skin patches, implanted or injectable products, intrauterine system [IUS], intrauterine device [IUD]) * Bilateral tubal occlusion * Vasectomized partner, provided that the partner is sole male sexual partner and absence of sperm confirmed * Sexual abstinence
• WOCBP must have a negative serum or urine pregnancy test within 28 days to confirm eligibility
• Women must not be breastfeeding
• Willingness to adhere to the study visit schedule and the prohibitions and restrictions specified in this protocol
• Written informed consent obtained from subject and ability for subject to comply with the requirements of the study

Exclusion Criteria

• Medical history and concurrent diseases * Subjects with active, known autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll * Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results * Known history of human immunodeficiency virus (HIV) * Known history of hepatitis B or hepatitis C * History of second malignancy (except non-melanomatous skin cancers and second malignancies not requiring active treatment), unless potentially curative treatment has been completed with no evidence of malignancy for 2 years * History of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease * Active infection requiring systemic therapy * Known history of active tuberculosis (TB) (Bacillus tuberculosis)
• Contraindication to additional radiation as determined by the treating radiation oncologist
• Prohibited treatments and/or therapies * Any live vaccine or live-attenuated vaccine within 30 days prior to the first dose of pembrolizumab. Administration of killed vaccines allowed * Prior therapy with an anti-PD-1, anti PD-L1, or anti-PD-L2 agent, or agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137) * Prior systemic anti-cancer therapy including investigational drug within 4 weeks, or 5 half-lives (whichever is shorter), prior to first dose of pembrolizumab * Prior radiotherapy within 2 weeks of first dose of pembrolizumab. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous system (CNS) disease * Systemic corticosteroid dexamethasone > 2 mg/day or equivalent at screening only
• Currently participating in an investigational study or use of an investigational agent within 4 weeks prior to first dose of pembrolizumab
• Immunodeficiency diagnosis or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
• Severe hypersensitivity (>= Grade 3) to pembrolizumab and/or any of its excipients
• Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Has had an allogenic tissue/solid organ transplant
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator