Phase I dose escalation of the Exportin 1 inhibitor, Selinexor, in combination with chemoradiation in patients with newly diagnosed glioblastoma

Purpose: Glioblastoma (GBM) remains associated with poor outcomes, with most recurrences occurring within the high-dose radiation field, suggesting persistent radioresistance. Exportin 1 (XPO1) inhibition with Selinexor has demonstrated radiosensitizing effects in preclinical models. We conducted a phase I trial to evaluate the safety, tolerability, and preliminary efficacy of Selinexor in combination with standard chemoradiation for newly diagnosed GBM. Methods: This investigator-initiated phase I dose-escalation trial (3+3 design) enrolled adults with newly diagnosed GBM or gliosarcoma. Patients received standard radiotherapy (60 Gy in 30 fractions) with concurrent temozolomide and escalating doses of Selinexor. Three dose levels were evaluated: 80 mg weekly (weeks 1, 2, 4, 5); 60 mg twice weekly (weeks 1, 2, 4, 5); and 60 mg twice weekly (weeks 1-6) throughout radiotherapy. The primary endpoint was determination of the maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs). Secondary endpoints included progression-free survival (PFS), overall survival (OS), patterns of failure, and patient-reported outcomes (MDASI-BT). Results: Eleven patients were enrolled. Median age was 58 years, and median KPS was 90. The MTD was established at Selinexor 60 mg twice weekly during weeks 1, 2, 4, and 5 of chemoradiation. Dose level 3 exceeded the MTD with two DLTs. Treatment compliance was high, with minimal missed radiotherapy fractions. Median PFS was 15.9 months (95% CI, 6.2 28.5), and median OS was 17.4 months (95% CI, 14.1 not reached). Most recurrences were central (5/6 evaluable patients). Notably, multiple cases of delayed pseudoprogression were observed at 5, 9, 10, and 23 months post-radiotherapy. Patient-reported symptom burden remained stable over time. Conclusions: Selinexor can be safely combined with standard chemoradiation in patients with newly diagnosed GBM, with an MTD of 60 mg twice weekly during select treatment weeks. Preliminary efficacy signals and an increased incidence of delayed pseudoprogression suggest a potential radiosensitizing effect. These findings support further investigation of Selinexor in larger, prospective studies.