• Patients must have histologically confirmed World Health Organization (WHO) grade 2-4 glioma, isocitrate dehydrogenase (IDH) wild type (WT) (by immunohistochemistry \[IHC\] R132H negative \[neg\] or sequencing). Astrocytoma with molecular features of glioblastoma (GBM). Confirmed diagnosis via molecular testing

• Patients must have an established diagnosis of recurrent glioblastoma and:

‣ Group 1 and 2: recurrent glioblastoma

⁃ Group 3: Surgically amenable recurrent glioblastoma

• Patients must have stable or decreasing dose of corticosteroids equivalent to ≤ 6 mg dexamethasone, for ≥ 7 days prior to registration

• Patients with disease that has progressed after a standard or investigational first-line therapy (e.g. radiotherapy \[RT\], RT plus temozolomide) with or without tumor treating fields therapy (TTFields)

‣ Note: Patients who have received fractionated first-line radiation therapy and no prior chemotherapy (e.g. as common practice for MGMT unmethylated tumors), or who have participated in an investigational protocol substituting TMZ for a novel agent are eligible

• Patients must be able to undergo contrast-enhanced magnetic resonance imaging (MRI)

• Patients must be age ≥ 18 years

• Patients must exhibit a Karnofsky performance status ≥ 70

• Leukocytes (white blood cells \[WBC\]) ≥ 3,000/mcL

• Absolute neutrophil count (ANC) ≥ 1,500/mcL

• Hemoglobin (Hgb) ≥ 8 g/dL (transfusion may be used for eligibility outside of 7 days)

• Platelets (PLT) ≥ 100,000/mcL (transfusion or growth factor may be used for eligibility outside of 7 days)

• Total bilirubin ≤ 2 x institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) ≤ 3 x institutional ULN

• Creatinine ≤ 1.5 x institutional ULN

• International normalized ratio (INR) ≤ 1.5 x ULN

• Prothrombin time (PT)/partial thromboplastin time (PTT) ≤ 1.5 x ULN

• 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 2B or better

• Patients of child-bearing potential (POCBP) must agree to use two forms of adequate contraception (hormonal or barrier method of birth control, abstinence) from time of informed consent and for the duration of study participation. Patients who can impregnate their partners must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) from time of informed consent and for the duration of study participation

‣ Should a patient become pregnant or suspect they are pregnant while they or their partner is participating in this study, they should inform their treating physician immediately.

⁃ Note: At the discretion of the investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.)

⁃ Note: A POCBP is any person with an egg-producing reproductive tract (regardless of gender, sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

• Has not undergone a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy

∙ Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months) (in patients \> 45 years of age in the absence of other biological or physiological causes)

‣ Potential POCBP who may be menopausal and are \< 55 years of age must have a serum follicle-stimulating hormone (FSH) level \> 40 mIU/mL to confirm menopause

⁃ Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff

• Patient must be willing and able to comply with the protocol for the duration of the study and provide written, signed, and dated informed consent prior to study registration.

‣ NOTE: No study-specific screening procedures may be performed until written consent has been obtained

• Patients must have the ability to understand and the willingness to sign a written informed consent document