Phase I trial combining sulfasalazine and gamma knife radiosurgery for recurrent glioblastoma

Recurrent glioblastoma (GBM) remains a therapeutic challenge with poor prognosis and limited treatment options. This phase I, open-label, dose-escalation trial investigates the safety and tolerability of combining sulfasalazine, a cystine/glutamate antiporter-inhibitor, with gamma knife radiosurgery (GKRS) for patients with recurrent GBM. Sulfasalazine is hypothesized to potentiate radiotherapy by depleting tumor cells of glutathione (GSH), thereby enhancing susceptibility to reactive oxygen species generated during irradiation. The study aims to establish the maximum tolerated dose (MTD) of sulfasalazine in combination with GKRS and explore preliminary efficacy signals through imaging and clinical endpoints.•Primary objective: Determine the MTD of sulfasalazine combined with GKRS and recommend a dose for future•phase II trials using the common toxicity criteria for adverse events v4.0.•Secondary objectives: Assess changes in intratumoral GSH via GSH‑edited Magnetic Resonance Spectroscopy, tumor response by Response Assessment in Neuro‑Oncology criteria, metabolic response on Carbon-11 methionine positron emission tomography, quality of life, progression free and overall survival.•Design: Open-label, dose-escalation study enrolling 12-24 patients with recurrent GBM eligible for GKRS.Patients receive sulfasalazine for 3 days prior to GKRS, followed by 12 months of monitoring for adverse events, imaging biomarkers, radiological and survival outcomes. This trial will provide safety data and inform the potential of sulfasalazine as a radiosensitizer in GBM treatment.