ADI-PEG 20 Plus Radiotherapy and Temozolomide in Subjects with Glioblastoma Multiforme

Inclusion Criteria:

1. Newly diagnosed, histologically confirmed glioblastoma, IDH-wildtype and the WHOGrade 4 of astrocytoma, IDH-mutant by WHO 2021 classification of brain tumors,non-resectable or partially resected or resected.

2. Age 20 - 75 years.

3. Karnofsky Performance Status (KPS) ≥ 60.

4. Expected life expectancy ≥16 weeks.

5. Stable or decreasing corticosteroids (5 mg/day dexamethasone or equivalent) within 5days before the first dose of ADI-PEG 20.

6. No prior systemic therapy, immunotherapy, investigational agent, or radiationtherapy.

7. Recovered from any prior surgery and no major surgery within 2 weeks of initiatingtreatment (other than GBM surgery). Surgery for placement of vascular access devicesis acceptable.

8. Female subjects and male subjects must be asked to use appropriate contraception forboth the male and female for the duration of the study and for at least 30 daysafter the last administration of ADI-PEG 20 or placebo and at least 6 months afterthe last administration of TMZ. Male partners of female subjects and female partnersof male subjects must agree to use two forms of contraception or agree to refrainfrom intercourse for the duration of the study if they are of childbearingpotential. Females of childbearing potential must not be pregnant at the start ofthe study, and a serum human chorionic gonadotropin (HCG) pregnancy test must benegative before entry into the study. If positive HCG pregnancy test, furtherevaluation to rule out pregnancy must be performed according to GCP before thissubject is deemed eligible. Females not of childbearing potential must bepost-menopausal (defined as cessation of regular menstrual period for at least 12months).

9. Informed consent must be obtained prior to study initiation.

10. No concurrent investigational studies are allowed.

11. Absolute neutrophil count (ANC) ≥ 1500/μL.

12. Platelets ≥ 100,000/μL.

13. Serum uric acid ≤ 8 mg/dL (with or without medication control).

14. Creatinine clearance must be ≥ 40 mL/min/1.73 m2 (calculated using theCockcroft-Gault equation: calculated creatinine clearance = (140-age (yrs)) × bodyweight (kg) (×0.85 if female) / 72 × serum creatinine (mg/dl).

15. Total bilirubin ≤ 2 x upper limit of normal.

16. ALT and AST ≤ 3 x upper limit of normal, unless liver metastases present then ≤ 5 xupper limit normal.

Exclusion Criteria:

1. Serious infection requiring treatment with systemically administered antibiotics atthe time of study entrance, or an infection requiring systemic antibiotic therapywithin 7 days prior to the first dose of study treatment.

2. Pregnancy or lactation.

3. Expected non-compliance.

4. Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure (New York Heart Association ClassIII or IV), cardiac arrhythmia, or psychiatric illness, social situations that wouldlimit compliance with study requirements.

5. Subjects with history of another primary cancer, including co-existent secondmalignancy, with the exception of: a) curatively resected non-melanoma skin cancer;b) curatively treated cervical carcinoma in situ; or c) other primary solid tumorwith no known active disease present or in the opinion of the investigator will notaffect patient outcome.

6. Subjects who had been treated with ADI-PEG 20 previously.

7. History of uncontrolled seizure disorder not related to underlying cancer.

8. Known HIV positivity, or active hepatitis B infection, or active hepatitis Cinfection (testing not required).

9. Allergy to pegylated compounds.

10. Allergy to E. coli drug products (such as GMCSF).

11. Allergy to TMZ or any of its components.

12. History of hypersensitivity to dacarbazine.

13. Placement of Gliadel wafer at surgery.

14. Having a co-existing condition requiring systemic treatment with eithercorticosteroids or immunosuppressive medication.