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

Bente Sandvei Skeie; Alexander Richard Craig-Craven; Eli Renate Grüner; Martin Biermann; Frank Riemer; Sidsel Bragstad; Shahin Sarowar; Maziar Behbahani; Linda Sleire; Thomas Schwarzlmüller; Dorota Goplen; Jan Ingeman Heggdal; Jonathan P S Knisely; Michael Schulder; Geir Egil Eide; Christopher G Filippi; Per Øyvind Enger

doi:10.1016/j.redox.2026.104241

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

Redox Biol. 2026 May 30:95:104241. doi: 10.1016/j.redox.2026.104241. Online ahead of print.

Authors

Bente Sandvei Skeie¹, Alexander Richard Craig-Craven², Eli Renate Grüner³, Martin Biermann⁴, Frank Riemer⁵, Sidsel Bragstad⁶, Shahin Sarowar⁷, Maziar Behbahani⁸, Linda Sleire⁹, Thomas Schwarzlmüller¹⁰, Dorota Goplen¹¹, Jan Ingeman Heggdal¹², Jonathan P S Knisely¹³, Michael Schulder¹⁴, Geir Egil Eide¹⁵, Christopher G Filippi¹⁶, Per Øyvind Enger¹⁷

Affiliations

¹ Department of Neurosurgery, Haukeland University Hospital (HUS), Jonas Lies vei 65, Bergen, 5021, Norway; Department of Biomedicine, University of Bergen (UiB), Jonas Lies vei 91, Bergen, Norway. Electronic address: bente.sandvei.skeie@helse-bergen.no.
² Department of Biological and Medical Psychology, UiB, Jonas Lies vei 91, Bergen, Norway; Department of Clinical Engineering, HUS, Jonas Lies vei 65, Bergen, 5021, Norway. Electronic address: alex.craven@uib.no.
³ Department of Physics and Technology, UiB, Jonas Lies vei 65, Bergen, 5021, Norway; Mohn Medical Imaging and Visualization Center, Department of Radiology, HUS, Jonas Lies vei 65, Bergen, 5021, Norway. Electronic address: renate.gruner@uib.no.
⁴ Nuclear Medicine and PET Centre, Department of Radiology, HUS, Jonas Lies vei 65, Bergen, 5021, Norway; Section for Radiology, Clinical Institute I, UiB, Jonas Lies vei 65, Bergen, 5021, Norway. Electronic address: martin.biermann@uib.no.
⁵ Mohn Medical Imaging and Visualization Center, Department of Radiology, HUS, Jonas Lies vei 65, Bergen, 5021, Norway. Electronic address: frank.riemer@uib.no.
⁶ Department of Neurosurgery, Haukeland University Hospital (HUS), Jonas Lies vei 65, Bergen, 5021, Norway. Electronic address: sidsel.bragstad@gmail.com.
⁷ Department of Biomedicine, University of Bergen (UiB), Jonas Lies vei 91, Bergen, Norway. Electronic address: shahin.sarowar@helse-bergen.no.
⁸ Department of Neurosurgery, Stavanger University Hospital, Armauer Hansens vei 30, Stavanger, 4011, Norway. Electronic address: mazi@sus.no.
⁹ Laboratory Medicine and Pathology, HUS, Jonas Lies vei 65, Bergen, 5021, Norway. Electronic address: linda.sleire@helse-bergen.no.
¹⁰ Nuclear Medicine and PET Centre, Department of Radiology, HUS, Jonas Lies vei 65, Bergen, 5021, Norway. Electronic address: thomas.schwarzlmueller@gmail.com.
¹¹ Department of Oncology and Medical Physics, HUS, Jonas Lies vei 65, Bergen, 5021, Norway. Electronic address: dorota.katarzyna.pazdyk.goplen@helse-bergen.no.
¹² Department of Oncology and Medical Physics, HUS, Jonas Lies vei 65, Bergen, 5021, Norway. Electronic address: jihe@helse-bergen.no.
¹³ Department of Radiation Oncology, Amsterdam University Medical Center, Meibergdreef 9, Amsterdam, 1105 AZ, the Netherlands. Electronic address: j.p.knisely@amsterdamumc.nl.
¹⁴ Department of Neurosurgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 125 Community Dr, Great Neck, NY, 11021, USA. Electronic address: mschulder@northwell.edu.
¹⁵ Department of Neurosurgery, Haukeland University Hospital (HUS), Jonas Lies vei 65, Bergen, 5021, Norway. Electronic address: geir.egil.eide@helse-bergen.no.
¹⁶ Department of Radiology, The Hospital for Sick Children, 555 University Ave, Toronto, M5G 1X8, Canada. Electronic address: sairaallapeikko@gmail.com.
¹⁷ Department of Biomedicine, University of Bergen (UiB), Jonas Lies vei 91, Bergen, Norway; Department of Neurosurgery, Stavanger University Hospital, Armauer Hansens vei 30, Stavanger, 4011, Norway. Electronic address: per.enger@uib.no.

Abstract

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.

Keywords: Glioblastoma; High grade glioma; Radiosensitizer; Recurrence; Stereotactic gamma knife radiosurgery; Sulfasalazine.

Associated data

ClinicalTrials.gov/NCT04205357