A Comprehensive Multiomic Biomarker Evaluation Across Two Single-arm Cohorts to Elucidate Mechanisms of Response and Resistance in Recurrent/Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (HNSCC)

This investigator-initiated study is designed to conduct a comprehensive multiomic biomarker evaluation across two single-arm cohorts to elucidate mechanisms of response and resistance in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Cohort A will enroll approximately 20 patients. All participants will receive GSK5764227 monotherapy at a starting dose of 8 mg/kg Intravenously every 3 weeks (IV Q3W) in a 21-day treatment cycle. Cohort B will start only after Cohort A has been initiated, with enrollment of approximately 10 patients. All participants will receive a combination of GSK5764227 (8 mg/kg IV Q3W) and dostarlimab (500 mg IV Q3W). The study drug, GSK5764227, is a new kind of medicine known as an antibody drug conjugate (ADC). GSK5764227 binds to a substance known as B7-H3 that is found on the surface of tumor cells. Once GSK5764227 binds to B7-H3, it enters the tumor cell and releases a chemotherapy-type drug (known as GSK5757810) which has been shown to damage and kill tumor cells. The study treatment will generally continue until confirmed disease progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, unacceptable toxicity, withdrawal of participant consent, noncompliance, or Investigator decision based on clinical deterioration or other relevant factors. For participants receiving dostarlimab, treatment will not exceed a maximum duration of 24 months in the absence of prior progression. There is the possibility to continue treatment beyond initial progression at Study PI's judgment. This investigator-initiated phase II study is expected to require approximately 40 months from the time the first participant signs the informed consent form until the last participant completes their last study visit.