Phase 1 dose-escalation trial combining sulfasalazine and stereotactic radiosurgery in patients with recurrent glioblastoma.

Glioblastoma radioresistance is linked to glutathione, a key antioxidant protecting against oxidative stress. Sulfasalazine inhibits the xCT antiporter mediating cystine uptake required for glutathione synthesis in glioma, potentiating radiotherapy in preclinical studies. This trial evaluated safety and therapeutic potential of combining sulfasalazine with stereotactic radiosurgery (SRS) for recurrent glioblastoma. Adults with recurrences were enrolled in a 3 + 3 dose-escalation trial receiving 1.5, 3.0, 4.5, or 6.0 g sulfasalazine orally for 3 days before SRS. Primary endpoint was safety. Secondary endpoints included changes in quality of life (QOL), tumor glutathione-levels, metabolism, and volumes assessed via Functional-Assessment-of-Cancer-Therapy-Brain-questionnaire, glutathione-edited-MR-spectroscopy,11C-Methionine-PET, and MRI. Eleven eligible patients treated with GKRS only due to closed research facilities served as concurrent controls for time to local tumor progression, progression-free survival (PFS), and overall survival (OS). Twelve patients were enrolled and followed until death or consent withdrawal (n = 1). Of 20 adverse events, two were grade 3 (transient lymphocytopenia), four grade 2, and fourteen grade 1. QOL remained stable for 6 months (p = 0.292). Tumor glutathione-levels and metabolic activity were reduced on day 3 (p = 0.010) and 1 month (p = 0.052), respectively. Best RANO-responses were objective (5/11), stable (5/11) or progressive (1/11) for participants vs. stable (2/11) or progressive (9/11) for controls, p = 0.001. Participants had longer local tumor control (median difference: 5.3 months, 95% CI: 1.0-9.6, p < 0.001) and PFS (1.7 months, 95% CI: 0.3-3.0, p = 0.009), with equivalent OS (p = 0.915). In conclusion sulfasalazine and SRS were well tolerated, reducing intratumoral glutathione-levels and associated with more durable local control than SRS alone supporting phase II investigation. TRIAL REGISTRATION: NCT04205357.