A Phase I/II Study of IVONESCIMAB in Recurrent Glioblastoma

Inclusion Criteria:

1. Age ≥18 years

2. Karnofsky Performance Status (KPS) of 60 or greater

3. Recurrent supratentorial Glioblastoma that has progressed following standardtherapy; patients must have previously been treated with radiation with or withouttemozolomide.

4. Patients will be eligible at first or second recurrence.

5. Patients must be greater than 12 weeks from completion of initialchemoradiation at the time of progression, with the exception that patientswith biopsy-confirmed recurrent disease prior to this time window can beenrolled.

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

7. Measurable or evaluable disease per RANO criteria

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

9. Adequate Organ Function, with screening labs performed within 14 days of treatmentinitiation: a. Hematology (no blood transfusions or growth factor therapy used within 7 days ofthe screening CBC): i. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L ii. Plateletcount ≥ 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 glomerularfiltration rate (eGFR) value ≥50 mL/min using the Chronic Kidney DiseaseEpidemiology Collaboration (CKD-EPI) equation (adjustment by BSA is not required foreGFR) CrCL or eGFR can be determined using the calculator from the National KidneyFoundation website (www.kidney.org). ii. Urine protein < 2+ or 24-hour urine protein quantification < 1.0 g or Urineprotein/Creatinine ratio ≤ 1mg/mg (≤ 113.2mg/mmol) c. Liver: i. Serum totalbilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); For patients withconfirmed/suspected Gilbert syndrome, TBIL ≤3 × ULN ii. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN d. Coagulation: prothrombintime (PT) or international normalized ratio (INR)

• 1.5 × ULN, and partial prothrombin time (PTT) or activated partialthromboplastin time (aPTT) ≤ 1.5 × ULN (unless abnormalities are unrelated tocoagulopathy or prophylactic coagulation)

8. Female patients of childbearing age must have negative serum pregnancy test resultsbefore randomization or per region-specific guidance documented in the informedconsent and a negative urine pregnancy test on the day of first dose prior todosing.

9. Female patient of childbearing potential having sex with an unsterilized malepartner must agree to use a highly effective method of contraception from thebeginning of screening until 120 days after the last dose of the ivonescimab.

10. Male patients of childbearing potential having sex with a female partner ofchildbearing potential must agree to use an effective method of contraception fromthe beginning of screening until Day 120 after the last dose of ivonescimab.

11. Ability to understand and willingness to sign informed consent form prior to theinitiation of study and any study procedures.

12. Participants with cognitive impairment may be enrolled. The formal consent forsuch participants will be obtained from their legally authorizedrepresentative. However, participants will be informed about the research tothe maximum extent compatible with their understanding. Assent will be obtainedfrom such participants who will sign and date the consent form if capable.

13. Non-English speakers are allowed to enroll provided consent and all visits willbe conducted with a medical interpreter.

Exclusion Criteria:

1. Major surgical procedures or serious trauma, or plans for major surgical procedureswithin 4 weeks after the first dose (as determined by the investigator). Minor local procedures (excluding central venous catheterization and portimplantation).

2. Currently pregnant or breastfeeding.

3. History of bleeding tendencies or coagulopathy and/or clinically significantbleeding symptoms, including but not limited to: a. Significant intracranial hemorrhage

4. Note: Patients with clinically asymptomatic presence of hemosiderin, resolvingpostoperative changes or punctate intratumoral hemorrhage are permitted

5. Gastrointestinal bleeding b. Hemoptysis (defined as coughing up ≥ 0.5 teaspoon of fresh blood or small bloodclots) Note: transient hemoptysis associated with diagnostic bronchoscopy isallowed. c. Nasal bleeding /epistaxis (bloody nasal discharge is allowed) d. Needfor therapeutic anticoagulant therapy Note: Prophylactic anticoagulation for DVT/PEor to maintain venous patency is allowed.

6. Current hypertension with systolic blood pressure ≥ 150 mmHg or diastolic bloodpressure ≥ 100 mmHg after oral antihypertensive therapy

7. Is receiving dexamethasone >2mg daily, or the corticosteroid equivalent thereof.

8. History of major diseases, specifically:

9. Unstable angina, myocardial infarction, congestive heart failure (New YorkHeart Association [NYHA] classification ≥ grade 2) or vascular disease (eg,aortic aneurysm at risk of rupture), or other cardiac impairment that mayaffect the safety evaluation of the study drug (eg, poorly controlledarrhythmias, myocardial ischemia)

10. History of esophageal gastric varices, severe ulcers, wounds that do not heal,abdominal fistula, intra-abdominal abscesses, or acute gastrointestinalbleeding

11. History of arterial thromboembolic event, venous thromboembolic event of Grade 3 and above as specified in National Cancer Institute (NCI) Common TerminologyCriteria for Adverse Events (CTCAE) 5.0, transient ischemic attack,cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy

12. Acute exacerbation of chronic obstructive pulmonary disease within 4 weeksbeforerandomization

13. History of perforation of the gastrointestinal tract and/or fistula, history ofgastrointestinal obstruction (including incomplete intestinal obstructionrequiring parenteral nutrition), extensive bowel resection (partial colectomyor extensive small bowel resection)

14. History of other malignancy diagnosed or requiring treatment within the past 3 yearsprior to enrolment, with the exception of those with negligible expected risk ofmetastasis or death (including adequately treated non- melanoma skin cancer orcervical carcinoma in situ).

15. History of prior treatment of GB with anti-VEGF and/or anti-PD-1/PDL-1 agents,including monotherapy with either category or combinations thereof.

16. Has received prior interstitial brachytherapy, interstitial thermal therapy,implanted chemotherapy, or therapeutics delivered by local injection or convectionenhanced deliver. Prior treatment with Gliadel ® wafers will be excluded. Concurrentuse of devices such as Tumor Treating Fields is not permitted.

17. Has known leptomeningeal disease, gliomatosis cerebri, extracranial disease, ormulticentric disease (regionally multifocal enhancing disease with continguousT2/FLAIR is permitted to be enrolled)

18. Uncontrolled seizures after best medical therapy or other neurological conditionsincluding clinically significant autoimmune neurological disorders which canincrease risk for adverse effects or confound assessment of study outcomes asdetermined by the treating physician and PI

19. History of clinically significant autoimmune disease including but not limited tosystemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease,vascular thrombosis associated with antiphospholipid syndrome, granulomatosis withpolyangiitis, Sjogren's syndrome, GuillainBarré syndrome, multiple sclerosis,vasculitis or glomerulonephritis

20. Patients with a history of autoimmune hypothyroidism may be eligible if on astable dose of thyroid replacement hormone

21. Patients with controlled Type 1 diabetes mellitus may be eligible if on astable insulin regimen

22. Patients with dermatologic disorders (e.g., eczema) may be eligible if wellcontrolled at baseline and not requiring systemic treatment or other treatmentsbeyond low potency topical steroids

23. Has contraindication for undergoing MRI scans or receiving MRI contrast.

24. History of stroke or TIA within 6 months prior to study enrolment.

25. Imaging during the screening period shows that the patient has:

26. Radiologically documented evidence of major blood vessel invasion or encasementby cancer

27. Radiographic evidence of intratumor cavitation