Safety and Efficacy of CTX-009 With or Without CTX-471 for Recurrent Glioblastoma

Inclusion Criteria: * Histologically or radiographically confirmed recurrent CNS WHO grade 4 IDH wild-type glioma following standard of care treatment including radiation, chemotherapy, and/or tumor-treating fields. No more than 2 recurrences are allowed. * Patients may receive palliative treatment for recurrent disease prior to study enrollment with surgery or laser thermal ablation but must wait at least 4 weeks post-procedure to start study drug(s) and must have recovered from all procedure-related complications. * At least 18 years of age. * KPS performance status ≥ 60% * Adequate bone marrow and organ function as defined below: * Absolute neutrophil count ≥ 1.0 K/cumm * Platelets ≥ 75 K/cumm * Hemoglobin ≥ 8.0 g/dL * Total bilirubin ≤ 1.5 x IULN, unless suspected or documented history of Gilbert's Syndrome, in which case ≤ 2.5 x IULN * AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN * Creatinine clearance \> 30 mL/min by Cockcroft-Gault * Urine Protein : Creatinine ratio (UPCR) \< 300 mg/g * QTcF \< 480 msec; in the setting of bundle branch block or other arrhythmia that makes QTcF unreliable, a JT interval \< 350 msec can be used as a substitute. * The effects of CTX-009 and CTX-471 on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 4 months after completion of study treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study or should a man suspect he has fathered a child, s/he must inform her treating physician immediately. * Resolution, or stable control with medical management, of all prior anti-cancer therapy toxicities to ≤ grade 1 per NCI-CTCAE v5.0. If the patient has had major surgery, 4 weeks must have elapsed from the date of surgery and the first dose of study drug(s). * Stable or decreasing dose of corticosteroids and anti-seizure medications for 7 days prior to start of study drug(s). For Arm 2: a maximum of 2 mg daily dose of dexamethasone or equivalent at time of study drug(s) initiation is allowed. * Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants. Exclusion Criteria: * Have progressed on prior anti-VEGF-A therapy (i.e., bevacizumab) or developed clinically significant adverse reaction to any anti-VEGF therapy (i.e., bevacizumab, regorafenib) which led to discontinuation of treatment. Prior treatment with low dose anti-VEGF therapy for management of symptomatic vasogenic edema or radiation necrosis is permitted as long as progression was not noted while receiving treatment with the anti-VEGF agent, and is not needed for continued control of symptoms. A 4-week washout from last dose of low-dose anti-VEGF therapy is required. * Prior systemic anti-cancer therapy including: investigational agents or immunotherapy within 4 weeks (can consider 2 week interval for agents with known 5 half-lives \<14 days following discussion with study PI); chemotherapy within 4 weeks (6 weeks for BCNU or CCNU); or targeted therapy within 2 weeks prior to treatment. Note: participants must have recovered from all clinically significant AEs due to previous therapies to ≤ grade 1 or baseline. This does not include AEs deemed not clinically significant by treating physician (i.e., alopecia). Participants with endocrine-related AEs ≤ grade 2 requiring treatment or hormone replacement are eligible if controlled (i.e., clinically asymptomatic) on stable dose of replacement therapy. * Use of aspirin, NSAIDs, or other antiplatelet agents within 7 days of study drug(s) initiation. Regular use (i.e., daily) of these agents should be avoided while on study treatment. * Use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes within 7 days of study drug(s) initiation. Prophylactic dosing of DOAC, such as apixaban or edoxaban, or LMWH for patency of venous access devices is allowed (preference is given to DOAC over LMWH). * History of intraparenchymal or subdural hemorrhage. History of hemorrhage-related or gastroenterological disease including active hemorrhage, hemorrhagic diathesis, coagulopathy, or tumor in great arteries. History of clinically significant gastroenterological disease, such as peptic ulcer, GI bleeding, GI or non-GI fistula, perforation, abdominal abscess, percutaneous drains, clinical symptoms and signs of GI obstruction, need for parenteral hydration or nutrition, or inflammatory bowel disease (IBD). * History of unprovoked high-risk thromboembolic events. * A history of the following cardiovascular diseases in the past 5 years (a case-by-case evaluation can be considered in consultation with the study PI): * Congestive heart failure that corresponds to Class II or a higher class under NYHA classification or \< 50% of LVEF * Uncontrolled hypertension (140/90 mmHg despite best care including anti-hypertensive medications). White coat hypertension is not exclusionary. * Hypertensive crisis or pre-existing hypertensive encephalopathy * Pulmonary hypertension * Myocardial infarction * Uncontrolled arrhythmia * Unstable angina * Significant vascular diseases (e.g., aortic aneurysm requiring surgery or recent peripheral artery thrombosis) within 6 months prior to study entry * For Arm 2: Prior treatment with other investigational immune-oncology therapies targeting CD137 (4-1BB). * For Arm 2: Systemic therapy with non-steroidal immunosuppressive agents within 7 days prior to first dose. Patients with a prior history of autoimmune disease not requiring immunosuppressive therapy may be eligible following discussion with the study PI. Topical, intranasal, intraocular, or inhaled corticosteroids and physiologic replacement for patients with adrenal insufficiency are allowed. * Prior solid organ or hematologic cell transplantation. * For Arm 2: Has received a live or live-attenuated vaccine within 30 days prior to the first dose. Note: administration of killed vaccines is allowed. * Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial. * A history of allergic reactions attributed to compounds of similar chemical or biologic composition to CTX-009 or CTX-471. * Active uncontrolled seizure disorder. * Active uncontrolled intercurrent illness including, but not limited to: infection, hypertension, open wound(s), or cardiac arrhythmia. Chronic illnesses controlled (i.e., clinically asymptomatic) with oral medications are allowed. * Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test within 7 days of first dose for Arm 1 or 72 hours of first dose for Arm 2. * HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing not required in the absence of known history of infection. * Evidence of chronic hepatitis B virus (HBV) that is detectable on suppressive therapy. Patients with evidence of chronic HBV infection with undetectable HBV viral load on suppressive therapy are eligible. HBV testing not required in the absence of known history of infection. * History of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible. HCV testing not required in the absence of known history of infection.