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

Technical Summary: Phase I Dose Escalation of Selinexor with Chemoradiation in Newly Diagnosed Glioblastoma

Problem Statement
Glioblastoma (GBM) continues to present with poor prognostic outcomes, with a median survival of approximately 16 months for newly diagnosed patients. Despite the standard of care involving maximal safe resection followed by radiotherapy and temozolomide (TMZ), the majority of recurrences occur within the high-dose radiation field, indicating persistent radioresistance. Previous attempts to improve outcomes through radiation dose escalation or altered fractionation have failed to yield significant survival gains and often increased toxicity. While the addition of TMZ improves survival, its specific role as a radiosensitizer remains uncertain. Consequently, there is a critical need for novel radiosensitizing agents that can enhance the efficacy of standard chemoradiotherapy (CRT) without compromising safety. Exportin 1 (XPO1), a key mediator of nuclear export, is overexpressed in GBM and associated with poor outcomes. Preclinical models suggest that inhibiting XPO1 with Selinexor restores the nuclear retention of tumor suppressor proteins and ribosomal RNAs, thereby enhancing radiosensitivity, particularly in glioblastoma stem-like cells. However, the safety and tolerability of combining Selinexor with standard CRT in newly diagnosed GBM patients had not been previously evaluated.

Methodology
This was an investigator-initiated, prospective Phase I dose-escalation trial (NCT04216329) conducted at the National Institutes of Health (NIH). The study utilized a standard 3+3 design to determine the Maximum Tolerated Dose (MTD) of Selinexor when administered concurrently with standard CRT.

• Population: Eleven adults (age >18) with newly diagnosed GBM or gliosarcoma, Karnofsky Performance Status (KPS) ≥70, and within 8 weeks of surgical resection were enrolled.
• Intervention: All patients received standard radiotherapy (60 Gy in 30 fractions via IMRT/VMAT) with concurrent daily TMZ (75 mg/m²). Selinexor was administered orally at escalating dose levels:
  • Dose Level 1 (DL1): 80 mg once weekly (weeks 1, 2, 4, 5).
  • Dose Level 2 (DL2): 60 mg twice weekly (weeks 1, 2, 4, 5).
  • Dose Level 3 (DL3): 60 mg twice weekly (weeks 1–6).
  • Prophylactic antiemetics (5-HT3 antagonist and olanzapine) were provided. Adjuvant TMZ (150–200 mg/m²) was administered for a minimum of 6 months post-RT.
• Endpoints: The primary endpoint was the determination of the MTD based on Dose-Limiting Toxicities (DLTs) occurring from protocol entry to 30 days post-RT. Secondary endpoints included Progression-Free Survival (PFS), Overall Survival (OS), patterns of failure, and patient-reported outcomes (MDASI-BT).

Key Results

• Safety and MTD: The MTD was established at 60 mg twice weekly during weeks 1, 2, 4, and 5 of chemoradiation.
  • DL1 (80 mg weekly) showed no DLTs.
  • DL2 (60 mg twice weekly, weeks 1, 2, 4, 5) resulted in one DLT (hematologic toxicities including neutropenia and thrombocytopenia) among six patients.
  • DL3 (60 mg twice weekly, weeks 1–6) exceeded the MTD, with two patients experiencing DLTs (severe hematologic toxicities).
  • Treatment compliance was high, with minimal missed radiotherapy fractions (only one fraction missed across all 11 patients) and high adherence to Selinexor and TMZ.
• Efficacy Signals:
  • Survival: The median Overall Survival (OS) was 17.4 months (95% CI, 14.1–not reached), and median PFS was 15.9 months (95% CI, 6.2–28.5).
  • Recurrence Patterns: Among evaluable patients, most recurrences were central (within the high-dose field).
  • Pseudoprogression: A notable finding was the observation of delayed pseudoprogression in multiple cases at 5, 9, 10, and 23 months post-radiotherapy. Two patients with radiographic findings suggestive of progression at 5 and 23 months were confirmed to have no tumor upon clinical follow-up or surgical resection, respectively.
• Patient-Reported Outcomes: Symptom burden, as measured by the MDASI-BT, remained stable over time, with no statistically significant increases in scores during follow-up.

Significance and Claims
The authors conclude that Selinexor can be safely combined with standard chemoradiation in patients with newly diagnosed GBM, with a defined MTD of 60 mg twice weekly during specific treatment weeks. The study establishes a foundation for further investigation by demonstrating that the combination is feasible and generally well-tolerated.

The paper claims that the preliminary efficacy signals, specifically the median PFS of 15.9 months (which is notably longer than historical controls) and the increased incidence of delayed pseudoprogression, suggest a potential radiosensitizing effect of Selinexor. The authors posit that these findings support the hypothesis that XPO1 inhibition may enhance local treatment effects, potentially through mechanisms such as enhanced DNA damage response inhibition or modulation of inflammatory signaling. However, the authors explicitly state that the study was not powered to assess efficacy definitively and that the small sample size and lack of a control arm limit the interpretation of survival data. They emphasize that the observed delayed pseudoprogression complicates radiographic interpretation and suggests a need for advanced imaging or biomarker-driven approaches in future trials to distinguish true progression from treatment effects. The study supports the rationale for larger, prospective studies to validate these findings and refine dosing strategies.