Glioma Clinical Trials

• Age ≥18 years

• Karnofsky Performance Status (KPS) of 60 or greater

• Recurrent supratentorial Glioblastoma that has progressed following standard therapy; patients must have previously been treated with radiation with or without temozolomide.

∙ Patients will be eligible at first or second recurrence.

‣ Patients must be greater than 12 weeks from completion of initial chemoradiation at the time of progression, with the exception that patients with biopsy-confirmed recurrent disease prior to this time window can be enrolled.

• Diagnosis of Glioblastoma IDH-wildtype, WHO Grade 4 consistent with WHO CNS 2021 criteria. This will include patients with a diagnosis of molecular glioblastoma.

• Measurable or evaluable disease per RANO criteria

• A baseline MRI Brain no more than 14 days prior to study enrollment

• Adequate Organ Function, with screening labs performed within 14 days of treatment initiation:

• a. Hematology (no blood transfusions or growth factor therapy used within 7 days of the screening CBC): i. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L ii. Platelet count ≥ 100 × 109/L iii. Hemoglobin ≥ 9.0 g/dL b. Kidneys: i. Creatinine clearance\* (CrCL) ≥ 50 mL/min using the Cockcroft-Gault formula or estimated glomerular filtration rate (eGFR) value ≥50 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (adjustment by BSA is not required for eGFR)

• CrCL or eGFR can be determined using the calculator from the National Kidney Foundation website (www.kidney.org).

• ii. Urine protein \< 2+ or 24-hour urine protein quantification \< 1.0 g or Urine protein/Creatinine ratio ≤ 1mg/mg (≤ 113.2mg/mmol) c. Liver: i. Serum total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); For patients with confirmed/suspected Gilbert syndrome, TBIL ≤3 × ULN ii. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN d. Coagulation: prothrombin time (PT) or international normalized ratio (INR)

⁃ 1.5 × ULN, and partial prothrombin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (unless abnormalities are unrelated to coagulopathy or prophylactic coagulation)

• Female patients of childbearing age must have negative serum pregnancy test results before randomization or per region-specific guidance documented in the informed consent and a negative urine pregnancy test on the day of first dose prior to dosing.

• Female patient of childbearing potential having sex with an unsterilized male partner must agree to use a highly effective method of contraception from the beginning of screening until 90 days after the last dose of the ivonescimab.

⁃ Male patients of childbearing potential having sex with a female partner of childbearing potential must agree to use an effective method of contraception from the beginning of screening until Day 90 after the last dose of ivonescimab.

⁃ Ability to understand and willingness to sign informed consent form prior to the initiation of study and any study procedures.

• Participants with cognitive impairment may be enrolled. The formal consent for such participants will be obtained from their legally authorized representative. However, participants will be informed about the research to the maximum extent compatible with their understanding. Assent will be obtained from such participants who will sign and date the consent form if capable.

∙ Non-English speakers are allowed to enroll provided consent and all visits will be conducted with a medical interpreter.