Repeated Superselective Intraarterial Cerebral Infusion (SIACI) of Bevacizumab With Temozolomide and Radiation Compared to Temozolomide and Radiation Alone in Newly Diagnosed GBM

Those randomized to the treatment group (IA BV+TMZ/RT )the experimental aspects will include:

• Subjects will first be treated with Mannitol prior to IA BV infusion. Mannitol is delivered IA, 12.5 mL over 2 minutes in order to disrupt the blood brain barrier. IA mannitol has been used in several thousand patients in previous studies for the IA delivery of chemotherapy for malignant glioma.
• Subjects will then be treated with repeated IA BV. Each patient will receive one dose of IA BV on day 30, followed by chemoradiation. IA BV will be repeated every three months for a total of 3 infusions.

Inclusion criteria

• Subject is a male or female 18 years of age or older.
• Subject has a confirmed diagnosis of GBM according to the 2021 WHO Classification of Tumors of the CNS. Accordingly, eligible GBM patients will comprise only IDH-wild type astrocytomas with microvascular proliferation or necrosis or one or more of 3 genetic parameters (TERT promoter mutations, EGFR gene amplification, or combined gain of entire chromosome 7 and loss of entire chromosome 10).
• Subject has a Karnofsky Performance Status (KPS) 70% or greater.
• Subject has a life expectancy of at least 6 months, in the opinion of the Investigator.
• Subject must be able to undergo MRI evaluation.
• Subject meets the following laboratory criteria:

i. White blood count ≥ 3,000/μL ii. Absolute neutrophil count ≥ 1,500/μL iii. Platelets ≥ 100,000/μL iv. Hemoglobin > 10.0 g/dL (transfusion and/or ESA allowed) v. Total bilirubin and alkaline phosphatase ≤ 2x institutional upper limit of normal (ULN) vi. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN vii. Blood urea nitrogen (BUN) and creatinine < 1.5 x ULN

• Females of reproductive potential must have a negative serum pregnancy test and be willing to use an acceptable method of birth control.
• Males of reproductive potential must be willing to use an acceptable method of birth control to ensure effective contraception with partner.
• Able to understand and willing to sign an institutional review board (IRB)-approved written informed consent document (legally authorized representative permitted).

Exclusion criteria

• Subject has initiated chemotherapy or radiation treatment for diagnosis of or GBM.
• Subject has an IDH mutant astrocytoma or other non GBM brain tumor according to the 2021 WHO classification of Tumors of the CNS.
• Subject intends to participate in another clinical trial
• Subject has an active infection requiring treatment.
• Subject has radiographic evidence of multi-focal disease or leptomeningeal dissemination.
• Subject has a history of other malignancy unless the patient has been disease-free for at least 5 years. Adequately treated basal cell carcinoma or squamous cell skin cancer is acceptable regardless of time, as well as localized prostate carcinoma or cervical carcinoma in situ after curative treatment
• Subject has a known positive test for human immunodeficiency virus infection, or active hepatitis B or hepatitis C infection.
• Subject has a history or evidence of any other clinically significant disorder, condition or disease that would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
• Subject, if female, is pregnant or is breast feeding.