TIP-20. A randomized European multicenter phase 2, double-blind, 2-arm study of sulfasalazine versus placebo combined with stereotactic radiosurgery in recurrent glioblastoma: the STARS trial protocol

Abstract Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, characterized by marked radioresistance and a median survival of less than 15 months despite multimodal therapy. Treatment options for recurrent GBM are limited, with no established standard of care. One mechanism of radioresistance involves elevated glutathione (GSH) levels, which neutralize reactive oxygen species generated by radiotherapy. GSH synthesis depends on cystine uptake via the xCT antiporter, which is upregulated in glioma cells. Sulfasalazine (SAS), an FDA-approved anti-inflammatory drug, inhibits xCT and has demonstrated radiosensitizing effects in preclinical models and a phase I trial. The STARS trial is a randomized, double-blind, phase 2 multicenter study evaluating the efficacy and safety of a short course of SAS (1.5 g/day for 3 days) combined with stereotactic radiosurgery (SRS) versus placebo plus SRS in patients aged 18 - 75 years with recurrent GBM. The primary endpoint is the 3-month local tumor control rate. A total of 108 participants will be randomized 1:1, stratified by center, to SAS or placebo arms, providing 80% power at a 5% significance level to detect a 25% absolute improvement in local control (85% vs. 60%). Secondary endpoints include overall survival, progression-free survival, quality of life, cognitive function, safety, and patient- and caregiver-reported outcomes related to daily functioning. Exploratory endpoints include changes in tumor and brain GSH levels via MR spectroscopy, metabolic alterations on PET-MRI, xCT expression in archival tumor tissue, correlations between microbiota, immune status, and treatment response, and development of an AI-based predictive model integrating multimodal trial data. The trial is currently under regulatory and ethical review in nine European Gamma Knife centers and is seeking funding.