Nivolumab and Multi-fraction Stereotactic Radiosurgery With or Without Ipilimumab in Treating Patients With Recurrent Grade II-III Meningioma

Inclusion Criteria:

• Patients must have histologically confirmed World Health Organization (WHO) gradeII-III meningioma which has relapsed after prior radiation therapy withradiologically progressive or recurrent disease

• Patients must have measurable disease, defined as at least 1 lesion that can beaccurately measured in at least one dimension as >= 1 cm on brain magnetic resonanceimaging (MRI) but with the maximum dimension =< 5 cm OR gross tumor volume < 20cm^3. All the relapsed disease would need to be eligible to be treated withreirradiation

• Patients must have at least one prior surgery with available archival formalin-fixedparaffin-embedded (FFPE) tumor blocks of the initial or recurrent meningioma. Ifthere are multiple tumor blocks from multiple surgeries, the most recent tumor block (and ideally of the relapsed tumor after initial radiation therapy) should besubmitted. If a tumor block is not available, an alternative of 20-30 unstainedslides may be submitted instead. Annotation regarding whether the tumor block isbefore or after initial radiation therapy should be provided

• Prior initial radiation therapy may include external beam radiation or radiosurgery,or combination of both. However, the total dose of prior radiation exposure to thesite of recurrent tumor (for consideration of re-irradiation) cannot be more than 70Gy. The duration since the previous radiation exposure to the site of reirradiationneed to be at least 6 months

• Age >= 18 years

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Leukocytes >= 3,000/mcL

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN

• Serum creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2 for patients with creatinine levels above 1.5 x institutionalnormal

• The effects of nivolumab and/or ipilimumab on the developing human fetus areunknown. For this reason and because radiation therapy is known to be teratogenic,women of childbearing potential (WOCBP) and men must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) prior tostudy entry and for the duration of study participation. WOCBP should use anadequate method to avoid pregnancy for 5 months after the last dose ofinvestigational drug. Women of childbearing potential must have a negative serum orurine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of humanchorionic gonadotropin [HCG]) within 24 hours prior to the start of nivolumab. Womenmust not be breastfeeding. Men who are sexually active with WOCBP must use anycontraceptive method with a failure rate of less than 1% per year. Men receivingnivolumab and who are sexually active with WOCBP will be instructed to adhere tocontraception for a period of 7 months after the last dose of investigationalproduct. Women who are not of childbearing potential (i.e., who are postmenopausalor surgically sterile as well as azoospermic men) do not require contraception

• Women of childbearing potential (WOCBP) is defined as any female who hasexperienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal.Menopause is defined clinically as 12 months of amenorrhea in a woman over 45in the absence of other biological or physiological causes. In addition, womenunder the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL

• WOCBP receiving nivolumab will be instructed to adhere to contraception for aperiod of 5 months after the last dose of investigational product. Menreceiving nivolumab and who are sexually active with WOCBP will be instructedto adhere to contraception for a period of 7 months after the last dose ofinvestigational product. These durations have been calculated using the upperlimit of the half-life for nivolumab (25 days) and are based on the protocolrequirement that WOCBP use contraception for 5 half-lives plus 30 days and menwho are sexually active with WOCBP use contraception for 5 half-lives plus 100days

• Should a woman become pregnant or suspect she is pregnant while she or herpartner is participating in this study, she should inform her treatingphysician immediately

• Ability to understand and the willingness to sign a written informed consentdocument or, if decision-making capacity is impaired, consent of a legallyauthorized representative (e.g., spouse, adult child, live-in caretaker).

Exclusion Criteria:

• Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas ormitomycin C) prior to entering the study

• Patients who have had radiation therapy (to the site of reirradiation) within 6months prior to entering the study

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1); however, alopecia, sensory neuropathy =<grade 2, or other =< grade 2 not constituting a safety risk based on theinvestigator's judgment are acceptable

• Patients who are receiving any other investigational agents

• Patients who have previous treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, oranti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cellco-stimulation or immune checkpoint pathways

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to nivolumab and/or ipilimumab

• History of severe hypersensitivity reaction to any monoclonal antibody

• Current use of immunosuppressive medication (EXCEPT for the following: Intranasal,inhaled, topical steroids, or local steroid injection [e.g. intra-articularinjection]; systemic corticosteroids at doses =< 4 mg/day of dexamethasone orequivalent; steroids as premedication for hypersensitivity reactions [e.g. computedtomography (CT) scan premedication])

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements. However, patients with human immunodeficiency virus (HIV)on stable therapy with minimal viral loads and patients with hepatitis B andhepatitis C who have received treatment with minimal viral loads will be eligible

• Pregnant women are excluded from this study because radiation therapy is teratogenicand that the effects of nivolumab and/or ipilimumab on the developing human fetusare unknown. Because there is an unknown but potential risk for adverse events innursing infants secondary to treatment of the mother with nivolumab and/oripilimumab, breastfeeding should be discontinued if the mother is treated withnivolumab and/or ipilimumab

• Patients with active autoimmune disease or history of autoimmune disease that mightrecur, which may affect vital organ function or require immune suppressive treatmentincluding systemic corticosteroids, should be excluded. These include but are notlimited to patients with a history of immune related neurologic disease, multiplesclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome,myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD),Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxicepidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndromeshould be excluded because of the risk of recurrence or exacerbation of disease.Patients with vitiligo, endocrine deficiencies including thyroiditis managed withreplacement hormones including physiologic corticosteroids are eligible. Patientswith rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasiscontrolled with topical medication and patients with positive serology, such asantinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for thepresence of target organ involvement and potential need for systemic treatment butshould otherwise be eligible

• Patients are permitted to enroll if they have vitiligo, type I diabetesmellitus, residual hypothyroidism due to autoimmune condition only requiringhormone replacement, psoriasis not requiring systemic treatment, or conditionsnot expected to recur in the absence of an external trigger (precipitatingevent)

• Prior organ transplantation including allogeneic stem cell transplantation

• Other severe acute or chronic medical conditions including immune colitis,inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis, or psychiatricconditions including recent (within the past year) or active suicidal ideation orbehavior, or laboratory abnormalities that may increase the risk associated withstudy participation or study treatment administration or may interfere with theinterpretation of study results and, in the judgment of the investigator, would makethe patient inappropriate for entry into this study

• Live vaccination within 4 weeks of the first dose of nivolumab and while on trial isprohibited except for administration of inactivated vaccines