This will be an open-label Phase 0/1 study that will enroll approximately 15 participants, 9 participants with recurrent WHO Grade 4 glioma (rGBM) and 6 participants with brain metastases, who will receive the investigational drug risvutatug rezetecan (GSK5764227), a B7-H3-targeted antibody-drug conjugate (ADC) with the GSK5757810 payload.
The trial will consist of a Phase 0 component (subdivided into Arms A and B) and an Expansion Phase 1 component. Participants with tumors demonstrating a positive pharmacokinetic (PK) response in the Phase 0 component will be eligible to enroll in the Expansion Phase to receive therapeutic dosing of risvutatug rezetecan.
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.
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).
Single group
Risvutatug rezetecan
DrugRisvutatug rezetecan will be administered intravenously.
Phase 0: Total, Cleaved, and Unbound GSK5757810 Payload Concentration in Tumor Tissue
The total, cleaved, and unbound GSK5757810 payload concentration in Gd enhancing and Gd non-enhancing tumor tissue collected during Phase 0 surgery from participants with rGBM, and Gd enhancing tumor tissue collected during Phase 0 surgery from participants with brain metastases, will be determined.
Phase 1: Incidence of Adverse Events as Assessed by CTCAE v5.0
Incidence of the following will be summarized: AEs, SAEs, and AEs of Special Interest (AESIs); treatment discontinuations, dose interruptions, and dose reductions due to AEs; changes in vital signs, body weight, laboratory tests, ECG, and ECOG performance status
Phase 0: Total, Cleaved, and Unbound GSK5757810 Payload Concentration in CSF
The total, cleaved, and unbound GSK5757810 payload concentration in CSF collected during Phase 0 surgery will be determined.
Phase 0: pH2AX and B7-H3 Expression Change in Tumor Tissue
The change in expression of pH2AX and B7-H3 in GSK5764227-treated rGBM and brain metastasis tissue collected during Phase 0 surgery compared to archival tissue (baseline).
Phase 1: Progression-Free Survival at 6 Months (PFS6)
PFS6 will be quantified and measured for participants in the expansion Phase 1 component. Disease recurrence will be determined by MRI response assessment in neuro-oncology v2.0 (RANO).
Phase 1: Overall Survival (OS)
OS will be quantified and measured for participants in the expansion Phase 1 component. Disease recurrence will be determined by MRI response assessment in neuro-oncology v2.0 (RANO).
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Nader Sanai
Lead sponsor
St. Joseph's Hospital and Medical Center, Phoenix
Sponsor institution
GlaxoSmithKline
Collaborator
