Testing the Combination of Anti-cancer Drugs Actimab-A and Cemiplimab (REGN2810) to Improve Outcomes for Patients With Recurrent Glioblastoma

Inclusion Criteria: * Patients must have histologically or cytologically confirmed glioblastoma isocitrate dehydrogenase wild type (IDH-WT) World Health Organization (WHO) grade 4 inclusive of gliosarcoma (Louis et al., 2021) * Note: Isocitrate dehydrogenase (IDH) status confirmed by immunohistochemistry (IHC) for IDH1 R132H + next-generation sequencing (NGS) for IDH1 and IDH2 hotspots * Evidence of recurrent disease (RD) that is measurable (1 x 1cm) at first or second relapse demonstrated by disease progression using Response Assessment in Neuro-Oncology 2.0 (RANO 2.0) criteria, unless the recurrence is outside the radiation field or has been histologically documented * Tumor O-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) methylation status must be available from any prior GBM tumor specimen; 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) * Previous first-line treatment with at least radiotherapy (prior dose ≥ 40 gray \[Gy\]) * Note: Prior temozolomide, prior tumor-treatment fields and/or Gliadel wafer (if placed at initial tumor resection) are allowed, but none of these are required * Last radiation ≥ 6 months (182 days) prior to enrollment if received ≥ 60 Gy or ≥ 3 months (84 days) if received \< 60 Gy to limit the risk of radiation necrosis * No previous treatment with anti PD1, PDL1, CTLA-4, or other immune checkpoint inhibitors * No tumor-directed therapy for most recent progression * Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of Actimab-A in combination with cemiplimab (REGN2810) in patients \< 18 years of age, children are excluded from this study * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%) * Absolute neutrophil count ≥ 1,500/mcL * Platelets ≥ 100,000/mcL * Hemoglobin ≥ 9 g/dL * Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN) (however, patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be enrolled) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 × institutional ULN * Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m\^2 * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within six (6) months are eligible for this trial * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial * Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better * The effects of Actimab-A and cemiplimab (REGN2810) on the developing human fetus are unknown. For this reason and because anti-PD-1 agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for at least six (6) months after completion of Actimab-A. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and six (6) months after completion of Actimab-A and cemiplimab (REGN2810) administration * Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives (LAR) may sign and give informed consent on behalf of study participants Exclusion Criteria: * Patients who have not recovered to grade 0 or 1 or pre-treatment baseline from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia * Patients who are receiving any other investigational agents * Presence of extracranial metastatic or leptomeningeal disease * History of allergic reactions attributed to compounds of similar chemical or biologic composition to Actimab-A and cemiplimab (REGN2810) * Patients being treated with systemic immunostimulatory agents (including, but not limited to, interferon \[IFN\]-α or interleukin \[IL\]-2) within four (4) weeks prior to cycle 1 day 1. The study principal investigator (PI) must be consulted if a patient was being treated with any antibody within four (4) half-lives of said antibody Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-alpha \[TNF-α\] agents) within two (2) weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: * Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study * Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study * Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous * Pregnant women are excluded from this study because cemiplimab (REGN2810) is an anti-PD-1 agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cemiplimab (REGN2810), breastfeeding should be discontinued if the mother is treated with cemiplimab (REGN2810). These potential risks also apply to Actimab-A * Early disease progression prior to three (3) months from the completion of radiotherapy * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy defined as dexamethasone \> 2 mg/day or bioequivalent for at least three (3) consecutive days within two (2) weeks of start of study drug * Has active autoimmune disease that has required systemic treatment in the past two (2) years * Prior administration of a radiopharmaceutical unless 10 or more effective half-lives have elapsed before injection of Actimab-A (Ac225-lintuzumab) * Previous treatment with bevacizumab for the treatment of glioblastoma with therapeutic intent, or with bevacizumab as supportive therapy (e.g., edema reduction) within six (6) weeks (42 days) of initiation of study treatment. This is approximately two (2) half-lives which is justified based on median time to rebound tumor progression following bevacizumab discontinuation (6.1 weeks), median time to clinical deterioration following bevacizumab discontinuation after disease progression from multiple studies indicating that washout periods longer than eight (8) weeks are unlikely to be tolerated, and perioperative outcome data after neoadjuvant bevacizumab demonstrating relative safety of surgical intervention at least four (4) weeks after bevacizumab discontinuation (Sener et al., 2024) * Patients who are unable to take spironolactone or eplerenone due to intolerance, allergy, drug-drug interactions, or for any other reason