Relatlimab or Urelumab Alone and in Combination with Nivolumab in Treating Patients with Recurrent Glioblastoma

Inclusion Criteria

• Patients must have histologically proven glioblastoma or gliosarcoma which is progressive or recurrent (per RANO criteria) following radiation therapy and temozolomide
• Tumor O-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) methylation status must be available; results of routinely used methods for MGMT methylation testing (e.g. mutagenically separated polymerase chain reaction [MSPCR] or quantitative polymerase chain reaction [PCR]) are acceptable
• Patients must have a tumor tissue form indicating availability of archived tissue from initial resection at diagnosis of glioblastoma completed and signed by a pathologist; availability of tissue is not a requirement for study participation
• Phase I patients must have measurable contrast-enhancing disease (defined as at least 1 cm x 1 cm) by magnetic resonance imaging (MRI) imaging within 21 days prior to starting treatment (patients may have gross total resection, but should have measurable disease post-operatively); patients must be able to undergo MRI of the brain with gadolinium
• Phase I patients must be maintained on a stable corticosteroid regimen (no increase for 5 days) prior to the baseline MRI
• Patients must be in first recurrence of glioblastoma following radiation therapy and temozolomide
• Patients must have recovered from severe toxicity of prior therapy; an interval of at least 12 weeks must have elapsed since the completion of radiation therapy or placement of Gliadel wafers, and at least 6 weeks must have elapsed from the last dose of temozolomide (TMZ); no prior therapies are allowed other than radiation, temozolomide, and Gliadel wafers (placed during the first surgery at diagnosis of GBM)
• Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be able to care for himself/herself with occasional help from others)
• Absolute lymphocyte count >= 1000/ul
• Absolute neutrophil count >= 1,500/ul
• Platelets >= 100,000/ul
• Hemoglobin >= 9 g/dl
• Total bilirubin =< institutional upper limit of normal (except for patients with Gilberts' syndrome who must have normal direct bilirubin)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal
• Creatinine =< institutional upper limit of normal OR creatinine clearance >= 60 ml/min/1.73 m^2 for patients with creatinine levels above institutional normal
• Activated partial thromboplastin time (APTT) or partial thromboplastin time (PTT) =< 1.5 x institutional upper limit of normal
• Patients must be able to provide written informed consent
• Women of childbearing potential must agree to have a negative serum pregnancy test within 24 hours prior to treatment start; women of childbearing potential must agree to use two methods of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study treatment, and through at least 5 months after the last dose of study drug; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; sexually active men of reproductive potential who are partners of women with reproductive potential must also agree to use adequate contraception prior to the study, for the duration of study participation, and through at least 7 months after the last dose of study drug
• Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder; patients with prior malignancies must be disease-free for >= five years
• INTRATUMORAL STUDIES PATIENTS:
• Patients on the Intratumoral Studies surgical arm must be undergoing repeat surgery that is clinically indicated as determined by their care providers, where a significant debulking or a gross total surgical resection of the contrast-enhancing area is intended

Exclusion Criteria

• Patients receiving any other investigational agents are ineligible
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to anti-LAG-3, anti-CD137, and anti-PD1 are ineligible; the investigator brochures can be referenced for more information
• Patients with active or a known history of known or suspected autoimmune disease are ineligible; subjects with type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, and skin disorders (vitiligo, psoriasis, or alopecia) not requiring systemic treatment, are permitted to enroll
• Patients with a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of study entry are ineligible. There are two exceptions to this criteria: * The participant is receiving corticosteroids or immunosuppressive medication for conditions other than their brain tumor * Participants that enroll in the surgical portion of this study (Group 1 and Group 2) are allowed to take steroids for their brain tumor as required
• Phase I patients must not be receiving greater than 1 mg dexamethasone/day (or an equivalent amount of an alternative corticosteroid) for at least 1 week prior to treatment start
• Phase I patients must have no evidence of significant mass effect, no midline shift, and no uncontrolled clinical signs of mass effect
• Patients must have no evidence of significant hematologic, renal, or hepatic dysfunction; patients with underlying hepatocellular disease should be given careful risk/benefit consideration prior to enrollment; patients with a history of any chronic hepatitis as evidenced by the following are ineligible: * Positive test for hepatitis B surface antigen (HBsAg) * Positive test for qualitative hepatitis C viral load (by PCR) (Note: subjects with positive hepatitis C antibody and negative quantitative hepatitis C by PCR are eligible; history of resolved hepatitis A virus infection is not an exclusion criterion) * History of alcoholic or non-alcoholic steatohepatitis (NASH), auto-immune hepatitis, or previous grade 3-4 drug-related hepatitis, or any form of chronic liver disease
• Patients must be hepatitis C virus (HCV) negative (by quantitative PCR [qPCR]) and hepatitis B virus core antibody (HBcAb) negative (no prior hepatitis B infection)
• Patients with a confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to signing informed consent are ineligible
• Patients with uncontrolled or significant cardiovascular disease including, but not limited to, any of the following are ineligible: * Myocardial infarction or stroke/transient ischemic attack (TIA) within the 6 months prior to consent * Uncontrolled angina within the 3 months prior to consent * Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes) * History of other clinically significant cardiovascular disease (i.e., cardiomyopathy, congestive heart failure with New York Heart Association [NYHA] functional classification III-IV, myocarditis and pericarditis, significant pericardial effusion, significant coronary stent occlusion, deep venous thrombosis, etc.) * Cardiovascular disease-related requirement for daily supplemental oxygen
• Corrected QT interval (QTc) prolongation > 480 msec
• Patients with other uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with these agents
• Patients with a known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) are ineligible