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

Phase 0: Patients with rGBM will enroll into Arm A. Arm A Cohort 1 will determine the optimal time interval (OTI) for surgery based on PK data assessed from two sub-cohorts (Cohort 1a and 1b). The OTI will be defined as the surgical time interval after dosing that corresponds to the highest median concentration of unbound risvutatug rezetecan payload in gadolinium (Gd) non enhancing rGBM tissue in either Cohort 1a or Cohort 1b. Arm A Cohort 2 will receive the IV infusion at the OTI schedule. Cohort 2 enrollment will begin once Arm A Cohort 1 enrollment is complete and the OTI has been determined. Patients with brain metastases will enroll into Arm B. Arm B will receive the IV infusion at the OTI schedule. Arm B enrollment will begin once Arm A Cohort 1 enrollment is complete and the OTI has been determined. After enrollment into Cohort 1 is complete, a written report will be submitted to the DSMB Chair (or qualified alternate) describing the time intervals, adverse events (AE) observed, and any safety reports. The DSMB Chair will review the report and provide written authorization to proceed with Arm A Cohort 2 and Arm B enrollment, or request more information within approximately two business days. Approval for enrollment initiation must be obtained prior to opening enrollment for Arm A Cohort 2 and Arm B. Only participants with tumors demonstrating positive PK response will proceed to the expansion Phase 1 component. Otherwise, participants will receive standard of care. Participants will complete the assessments and procedures noted for the End of Treatment (EOT) Visit. Participants will complete the 30-Day, 60-Day, and 90-Day Safety Follow-Up Visits and they will be monitored for survival as outlined in the "All Participants" section. To assess the PK and pharmacodynamic (PD) endpoints, blood, serum, cerebrospinal fluid (CSF), and brain tumor tissue will be collected intraoperatively (Gd enhancing and Gd non-enhancing tumor tissue will be collected and analyzed separately). Phase 1: Participants with tumors demonstrating positive PK response will continue risvutatug rezetecan treatment at the same dose received in Phase 0, administered once every three weeks (Q3W). Treatment will begin once the participant has recovered from surgery. Participants will receive risvutatug rezetecan until disease progression, unacceptable toxicity, death, withdrawal of consent, loss to follow-up, or study termination by the Sponsor. Participants will complete the assessments and procedures noted for the EOT Visit. Participants will complete the 30-day, 60-day, and 90-day Safety Follow-Up Visits and they will be monitored for survival as outlined in the "All Participants" section. All Participants: All participants will return to the clinic for safety monitoring per the schedule of activities following risvutatug rezetecan treatment discontinuation, and will be contacted approximately every 3 months for up to 12 months for survival data collection. Follow-up for long-term survival will begin after the final safety follow-up visit. MRI scans and RANO reviews will occur approximately every 2-3 months, per standard of care, to monitor disease progression. Participant Duration: Phase 0: The Phase 0 component will last up to approximately 2 months, starting at the 28-day screening window through the Post-Op Follow-Up Visit. Phase 1: Participants will take risvutatug rezetecan as long as the drug is tolerated and the Investigator believes the participant may be obtaining benefit. Treatment will continue until confirmed progression, unacceptable toxicity, death, withdrawal of consent, lost to follow-up, or end of treatment. All Participants: Participants will continue participating for 15 months following their last infusion of risvutatug rezetecan. Participants will return for a 30-day, 60-day, and 90 day Safety Follow-Up Visit. They will then be followed for survival for up to 12 months following the final Safety Follow-Up Visit.