A Phase 0/1 Clinical Trial With an Expansion Phase of GSK5764227, a B7-H3-Targeted Antibody-Drug Conjugate (ADC), in Patients With Recurrent Grade 4 Glioma and Patients With Brain Metastases

Inclusion Criteria: * 1\. Diagnosed with: (a) GBM according to the 2021 WHO criteria, who have progressed on or following standard of care therapy, including maximal safe resection (biopsy allowed if resection was deemed unsafe) and concurrent chemoradiation; OR (b) Brain metastasis requiring surgical resection, whether treated or untreated, and must have well-controlled systemic disease or NED other than the brain metastases, in the opinion of the patient's primary oncologist. * 2\. Has archival or biopsy brain tumor tissue available. * 3\. Has measurable disease (preoperatively) defined as at least one contrast-enhancing lesion with two perpendicular measurements of at least 1 cm. * 4\. Age ≥18 at time of consent. * 5\. Has a performance status of ≤2 on the ECOG scale. * 6\. Has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by the local laboratory for eligibility): * Adequate Bone Marrow Function: Absolute neutrophil count ≥1500/μL (≥1.5 x 109/L), Platelets (at time of surgery) ≥100,000/μL (≥100 x 109/L), Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L (Criteria must be met without erythropoietin dependency and without pRBC transfusion within prior 2 weeks.) * Adequate Hepatic Function: Total Bilirubin ≤1.5x ULN (Participants with Gilbert's syndrome with a total bilirubin \>1.5x ULN and direct bilirubin ≤1.5x ULN will be permitted.), AST (SGOT) ≤2.5x institutional ULN, ALT (SGPT) ≤2.5x institutional ULN (Participants with liver metastases with ALT ≤5x ULN will be permitted.) * Adequate Renal Function: eGFR ≥50 mL/min/1.73 m2 (Calculated as individualized eGFR using the CKD-EPI formula \[2021\]); If measured or calculated GFR (e.g., creatinine clearance; mGFR) is required or used: ≥60 mL/min * Adequate Metabolic Function: Albumin ≥2.8 g/dL * Adequate Coagulation: INR or PT and aPTT ≤1.5x ULN * 7\. For females of childbearing potential: (a) Must have a confirmed negative serum pregnancy test (β-hCG) before starting study treatment (within 24 hours of first infusion); in rare cases where hCG is suspected to be elevated in the absence of pregnancy (e.g., due to a tumor producing hCG), an ultrasound must be performed to rule out possible pregnancy. (b) Must use a highly effective method of contraception (with a failure rate of \<1% per year and low user dependency) for at least 28 days prior to treatment, and agree to use such a method during study participation and for an additional 8 months after final study drug administration. (c) Agrees not to breastfeed starting at screening, during study participation, and for 8 months after final study drug administration. (d) Agrees not to donate eggs (ova, oocytes) for the purpose of reproduction starting at screening, during study participation, and for 8 months after final study drug administration. * 8\. For females of non-childbearing potential, is no longer of childbearing potential due to surgical, chemical, or natural menopause. * 9\. For males: (a) Agrees not to donate sperm starting at screening, during study participation, and for 5 months after final study drug administration. (b) Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agrees to remain abstinent starting at screening, during study participation, and for 5 months after final study drug administration; OR Must use a male condom and their female partner must use an additional highly effective method of contraception (with a failure rate of \<1% per year and low user dependency) starting at screening, during study participation, and for 5 months after final study drug administration. * 10\. Agrees to adhere to Lifestyle Considerations throughout study duration. * 11\. Able and willing to comply with scheduled visits, treatment plans, laboratory tests and other procedures. * 12\. Understands the informed consent document and has voluntarily agreed to participate by giving written informed consent (personally or via legally authorized representative(s), and assent if applicable). Written informed consent for the protocol must be obtained prior to any screening procedures. If consent cannot be expressed in writing, it must be formally documented and witnessed, ideally via an independent trusted witness. Exclusion Criteria: * 1\. Evidence of leptomeningeal metastasis or spinal cord compression. * 2\. Unable to undergo through MRI of the brain with IV contrast. * 3\. Known active systemic bacterial infection (requiring IV antibiotics or fever \>38.5°C at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C \[for example, hepatitis B surface antigen positive\] (screening of viral infection is not required for enrollment). * 4\. Serious infections within 4 weeks prior to the first infusion of study drug, including but not limited to infectious complications, bacteremia, severe pneumonia treated with IV antibiotics for ≥2 weeks; active infections with therapeutic IV antibiotics within 2 weeks prior to the first infusion of study drug. (Individuals who are receiving or have received prophylactic antibiotics \[e.g., prophylaxis against urinary infections\] are allowed). * 5\. Known other concurrent severe psychiatric and/or an uncontrolled medical condition that, in the Investigator's judgement, would cause unacceptable safety risks, contraindicate participation in the clinical study, or compromise compliance with the protocol. * 6\. Have any unresolved toxicities from prior therapy greater than NCI-CTCAE v5 Grade 1 at the time of starting study treatment (exceptions include: alopecia, hearing loss, vitiligo, endocrinopathy managed with replacement therapy, Grade 2 neuropathy, and any chronic Grade 2 toxicities following discussion with the Principal Investigator). * 7\. Has received treatment with any of the following: * a. Orlotamab, enoblituz