MBG453, Spartalizumab, and Stereotactic Radiosurgery for the Treatment of Recurrent Glioblastoma

Inclusion Criteria

• Patients must provide written informed consent prior to any screening procedures
• Willing and able to comply with scheduled visits, treatment plan and laboratory tests
• Must have histologically proven World Health Organization (WHO) grade IV glioblastoma or gliosarcoma based on histopathological OR molecular criteria
• Patients tumor target (GTV) should be =< 5 cm maximum diameter (the target will include gross progressive tumor and/or surgical cavity. If surgery is performed, the portion of the wall of the surgical cavity that is included in the GTV radiotherapy target will be determined at the discretion of the treating physician as in routine clinical care)
• a) Must have received first-line multimodal therapy with surgery (resection or biopsy) followed by radiation and temozolomide (unless known MGMT promoter unmethylated) AND b) Must have completed at least 21 days of combination and temozolomide therapy (unless known MGMT promoter unmethylated. An interval of at least 12 weeks after the end of combination radiation therapy + temozolomide is required unless there is: i.) Histopathologic confirmation of recurrent tumor, or ii) new enhancement on magnetic resonance imaging (MRI) outside of the radiotherapy treatment field. (*NOTE: Patients treated with Optune device or who received Gliadel wafers placed during the first surgery are eligible
• Must have no more than 2 recurrences of either glioblastoma (GBM) or gliosarcoma. Recurrence must be confirmed by diagnostic biopsy/surgery with local pathology review OR contrast-enhanced MRI measurable by Response Assessment in Neuro-Oncology Criteria (RANO) criteria. (*NOTE: Patients diagnosed with WHO grade III that undergo surgical resection and are found to have WHO grade IV or gliosarcoma are considered eligible)
• Prior gamma knife, stereotactic radiosurgery, or other focal high-dose radiotherapy is allowed but the subject must have either histopathologic confirmation of recurrent tumor, or new enhancement on magnetic resonance imaging (MRI) outside of the radiotherapy treatment field
• Karnofsky performance status >= 70
• Must have ability to undergo MRI scans
• Must be > 30 days since last chemotherapy
• Must have recovered from severe toxicity of prior therapy. (NOTE: Patients who undergo surgical resection must have recovered from surgery (at least 2 weeks) before starting study treatment)
• White blood cell (WBC) >= 2,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 9.0 g/dL
• Lymphocytes > 500/mcL
• Total bilirubin =< 1.5 X institutional upper limit of normal
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 X institutional upper limit of normal
• Creatinine =< 1.5 X institutional upper limit of normal OR creatinine clearance (CrCl) >= 50 mL/min (using the Cockcroft-Gault formula)
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within -7 days prior to the start of therapy. Women must not be breastfeeding
• Women of child bearing potential (WOCBP) and men must use a reliable form of contraception during the study treatment period and for 150 days following the last dose of study drug. In order for a woman to be determined not of child-bearing potential, she must have >= 12 months of non-therapy-induced amenorrhea or be surgically sterile

Exclusion Criteria

• History of other malignancy, unless the patient has been disease-free for at least >= 5 years. Curatively treated basal or squamous cell carcinoma of the skin, totally excised melanoma of stage IIA or lower, low or intermediate-grade localized prostate cancer (Gleason sum =< 7), and curatively-treated carcinoma in situ of the cervix, breast, or bladder are allowed regardless
• Any known metastatic extracranial or leptomeningeal disease
• Evidence of acute intracranial / intra-tumoral hemorrhage
• History of organ or hematopoietic stem cell (HSC) transplant
• Receiving greater than 4 mg dexamethasone/day (or equivalent amount of an alternative corticosteroid) for a minimum of 5 days prior to screening visit. Subjects with an autoimmune condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of randomization. * NOTE: Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone or equivalent, are permitted in the absence of active autoimmune disease
• Prior treatment with immune-modulating therapy, other than steroids
• Prior or current treatment with bevacizumab therapy for any reason
• Pregnant or nursing (lactating) women
• Known positive history of human immunodeficiency virus (HIV), active hepatitis B, and/or active hepatitis C infection
• Subjects with active, or recent history of known or suspected autoimmune disease. Subjects with type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
• Major surgery, outside of a craniotomy/resection, within 2 weeks of the first dose of study treatment (mediastinoscopy, insertion of a central venous access device, and insertion of a feeding tube are not considered major surgery)
• Use of live or prohibited vaccines against infectious diseases (e.g. varicella, pneumococcus) within 4 weeks of initiation of study treatment. (NOTE: Inactivated seasonal influenza vaccines and coronavirus disease [COVID] vaccine[s] are permitted and do not require a 4-week waiting period before starting study treatment)
• Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results
• Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
• History of evidence upon physical/neurological examination of other central nervous system condition (i.e. seizures, abscess) unrelated to cancer, unless adequately controlled by medication or considered not potentially interfering with protocol treatment
• History of allergy or hypersensitivity to study drug components
• Prisoners or subjects who are involuntarily incarcerated
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g. infections disease) illness