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

• 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 neg on immunohistochemistry [IHC])
• Tumor with MGMT gene promoter unmethylated
• Availability of paraffin embedded tumor tissue for the study
• Patients must be enrolled within 5 weeks from completion of standard radiotherapy plus or minus 1-5
• Patients must have completed standard radiotherapy plus or minus temozolomide (TMZ) equivalent to approx. 60 grey (Gy), e.g., 30 x 2 Gy or 33 x 1.8 Gy per local practice
• Patients must be >= 18 years of age
• 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 residual tumor and/or resection cavity must allow for adequate coverage by the sonication field. Patients must have a surgical cavity peri-tumoral brain cavity and enhancing residual tumor at MRI performed at conclusion of radiation which should have a diameter =< 60 mm. 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
• Patients should be off steroids for >= 7 days prior to treatment start, at registration they must be on stable or decreasing doses of steroids equivalent to dexamethasone =< 6 mg. 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 Gilberts 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 (eGFRcr) =< 1.5 × IULN OR measured or calculated creatinine clearance >= 40 mL/min per institutional standard within 14 days prior to registration. Assessment method should be recorded
• Patients must agree to use adequate contraception: - (e.g. hormonal or barrier method of birth control; abstinence), 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 or DOX. Should a female patient become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. 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. 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)

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, BOT, BAL or DOX
• Patients with other contraindication to checkpoint inhibitor therapy (e.g., history of autoimmune disease, see full protocol for details)
• 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
• 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 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 pneumonitis or 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. Note: Exceptions to this requirement include adequately treated non-melanoma skin cancer or lentigo maligna or carcinoma in situ without evidence of disease
• Patients with known history of hypersensitivity reactions to perflutren lipid microsphere components or to any of the inactive ingredients in Definity (Registered Trademark) (European Brand name: Luminity [Registerd Trademark]) microbubble products