AGEN1571, Botensilimab, Balstilimab, and Liposomal Doxorubicin in Combination with Ultrasound-Mediated Blood Brain Barrier Opening for the Treatment of Patients with Newly Diagnosed Glioblastoma

Inclusion Criteria

• FOR NEOADJUVANT (WINDOW-OF-OPPORTUNITY) COHORT
• Clinical and radiologic evidence of high grade glioma
• Patient must be clinically stable without signs of mass effect on physical exam
• Tumor is amenable to surgical resection. (NOTE: If a biopsy or subtotal resection has been performed, high grade glioma [HGG] has been confirmed, and further resection is recommended, then the implant may be placed and resection performed after cycle 1. If no biopsy has been done, a biopsy will be taken to confirm HGG at the time of device placement and before starting cycle 1, with resection occurring after cycle 1)
• Treating surgeon has determined it is reasonable to wait to perform surgical resection
• Patient has not started concomitant radiation and chemotherapy (if biopsy or subtotal resection have been done)
• FOR ADJUVANT COHORT
• Patients must have pathologically proven glioblastoma (per World Health Organization [WHO] central nervous system [CNS] 2021 classification) IDH1/2 wild-type (at least demonstrated as IDH1 R132H negative [neg] on immunohistochemistry [IHC])
• Tumor with MGMT gene promoter unmethylated
• Availability of paraffin-embedded tumor tissue block for the study
• Patients must be enrolled within 5 weeks from completion of standard radiotherapy +/- temozolomide (TMZ) and have not started adjuvant treatment
• Patients must have completed standard radiotherapy equivalent to approximately 60 Gy, e.g., 30 x 2 Gy or 33 x 1.8 Gy per local practice
• FOR ALL PATIENTS
• Age >= 18 years
• Patients must have the ability to undergo contrast-enhanced MRI
• Patients must have an Eastern Cooperative Oncology Group (ECOG)/WHO performance status =< 2
• Size and location of the tumor/residual tumor and/or resection cavity must allow for adequate coverage by the sonication field. * Patients must have a peri-tumoral brain cavity and/or enhancing tumor/residual tumor which should have a diameter =< 60 mm on the most recent MRI ** Note: Confirmation of anatomical eligibility will be performed centrally upon review of MRI, and subject to tri-dimensional analysis for adequate coverage
• Patients must not have received prior treatment with immunotherapeutic agents for glioblastoma or other indications
• Absence of contraindication for immune checkpoint inhibitors per local standard operating procedures
• At time of registration, they must be on stable or decreasing doses of steroids equivalent to dexamethasone =< 6 mg/day * At the time of treatment start, patients should be off steroids for >= 3 days prior to treatment start * For the neoadjuvant cohort, a steroid dose equivalent to dexamethasone =< 4 mg/day is permissible * Note: Exceptions include steroids for substitution in the setting of adrenal insufficiency, and total dexamethasone dose =< 1 mg per day
• Patients must have the ability to understand and willingness to sign a written informed consent prior to registration on study
• Patients must be willing and able to comply with the protocol
• Leukocytes (WBC) >= 3,000/uL (within 14 days prior to registration)
• Absolute neutrophil count (ANC) >= 1,500/uL (within 14 days prior to registration)
• Hemoglobin (Hgb) >= 9.0 g/dL (no transfusions allowed) (within 14 days prior to registration)
• Platelets (PLT) >= 75,000/uL (no transfusions allowed) (within 14 days prior to registration)
• Total bilirubin =< 1.2 mg/dl (for Gilbert's syndrome elevated bilirubin will be allowed) (within 14 days prior to registration)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) =< 3 x institutional upper limit of normal (ULN) (within 14 days prior to registration)
• Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x institutional ULN (upper limit of normal) (within 14 days prior to registration)
• Creatinine clearance: calculated creatinine clearance >= 40 mL/min per institutional standard (within 14 days prior to registration)
• Patients must agree to use adequate contraception: (e.g. hormonal or barrier method of birth control), for a female of child-bearing potential (FOCBP), prior to study entry, for the duration of study participation, and for 6 months after the last dose of BOT, BAL, DOX, or AGEN1571 * Should a female patient, or a female partner of a patient become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician and study doctor immediately * Note: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: ** Has not undergone a hysterectomy 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) * Male patients with a female partner(s) of childbearing potential must agree to use highly effective contraceptive measures throughout the study starting with the screening visit through 90 days (3 months) after the last dose of study treatment is received. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner

Exclusion Criteria

• Multifocal tumor (unless all localized in a 60-mm diameter area accessible to ultrasound field) or tumor located in the posterior fossa
• Patients with prior allogenic organ transplant
• Patients who have uncontrolled epilepsy
• Patients who have received other investigational agents within 2 weeks of registration
• Patients who have received prior therapy with or have history of allergic reactions attributed to compounds of similar chemical or biologic composition to AGEN1571, BOT, BAL or DOX
• Patients with other contraindication to checkpoint inhibitor therapy (e.g., history of autoimmune disease)
• Patients who have an uncontrolled intercurrent illness
• Patients who are pregnant or nursing
• Patients who have a history of active malignancy other than the brain tumor within 12 months prior to registration * Note: Exceptions to this requirement include adequately treated non-melanoma skin cancer or lentigo maligna or carcinoma in situ without evidence of disease * Malignant disease other than a brain tumor that has completed treatment with curative intent >= 24 months are eligible. Patients with prior metastatic disease to the brain or CNS are not eligible
• Patients with known significant cardiac disease, e.g: * Diseases known to have right-to-left shunts, severe pulmonary hypertension (pulmonary artery pressure > 90 mmHg), or adult respiratory distress syndrome * Patients with symptomatic congestive heart failure, unstable angina pectoris or unstable cardiac arrhythmia
• Patients with additional medical conditions: * Medical need to continue uninterrupted antiplatelet or anti-coagulation therapy * Increased risk of wound dehiscence or infection, poor skin condition, and/or previously infected surgical field or any other condition that is of increased infectious risk in the opinion of the neurosurgeon * Hypertension grade 3 or higher without adequate control on medications * Active infection requiring systemic treatment * History of severe pneumonitis, adult respiratory distress syndrome, or interstitial lung disease * Patients with psychiatric illness/social situations that would limit compliance with study requirements
• Patients with any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient’s safety or study endpoints
• Patients with implants or devices that are not MRI compatible, or patients that are unable to undergo MRI for other reasons
• Patients with impaired thermo-regulation or temperature sensation
• Patients with known history of hypersensitivity reactions to perflutren lipid microsphere components or to any of the inactive ingredients in Definity® (European Brand name: Luminity®) microbubble products