Final Report on Clinical Outcomes and Tumor Recurrence Patterns of a Pilot Study Assessing Efficacy of Belinostat (PXD-101) with Chemoradiation for Newly Diagnosed Glioblastoma

Abstract

Glioblastoma (GBM) is highly aggressive and has a poor prognosis. Belinostat is a histone deacetylase inhibitor with blood-brain barrier permeability, anti-GBM activity, and the potential to enhance chemoradiation. The purpose of this clinical trial was to assess the efficacy of combining belinostat with standard-of-care therapy. Thirteen patients were enrolled in each of control and belinostat cohorts. The belinostat cohort was given a belinostat regimen (500-750 mg/m² 1×/day × 5 days) every three weeks (weeks 0, 3, and 6 of RT). All patients received temozolomide and radiation therapy (RT). RT margins of 5-10 mm were added to generate clinical tumor volumes and 3 mm added to create planning target volumes. Median overall survival (OS) was 15.8 months for the control cohort and 18.5 months for the belinostat cohort (p = 0.53). The recurrence volumes (rGTVs) for the control cohort occurred in areas that received higher radiation doses than that in the belinostat cohort. For those belinostat patients who experienced out-of-field recurrence, tumors were detectable by spectroscopic MRI before RT. Recurrence analysis suggests better in-field control with belinostat. This study highlights the potential of belinostat as a synergistic therapeutic agent for GBM. It may be particularly beneficial to combine this radio-sensitizing effect with spectroscopic MRI-guided RT.

Keywords: epigenetic drug; glioblastoma; histone deacetylase; magnetic resonance spectroscopy; radiation sensitizer.

Figure 1

One-year timeline of chemotherapy, intravenous belinostat, and radiation for patients in NCT02137759.

Figure 2

(A) Overall Survival (OS) Kaplan-Meier Survival Curves. The median OS for the control and belinostat cohorts was 15.8 and 18.5 months, respectively (p = 0.53), for all patients. (B) Progression free survival (PFS) for all patients. The median PFS for control and belinostat cohorts was 9.0 months and 9.3 months, respectively (p = 0.75).

Figure 3

T1 post-contrast imaging in three patients, by horizontal row, with out of field recurrence in cohort 2. For each patient, the enhancing recurrence contour (rGTV) encompasses lesion that has spread outside the extent of radiation treatment targets PTV1 (guided by T2/FLAIR) or PTV2 (guided by T1w-CE).

Figure 4

Pre-RT sMRI scans suggest out-of-field recurrence in the belinostat cohort with tumor infiltration beyond what is shown in standard imaging (indicated by red arrows). (A) This patient had two-fold Cho/NAA elevation that had spread contralaterally. While pre-RT standard imaging failed to detect this, FLAIR hyperintensity at recurrence mimics the direction of tumor infiltration detected by pre-RT sMRI. (B) The second patient had tumor infiltration across the midline that wasn’t detected by pre-RT standard imaging. Lesions at recurrence in both T1w-CE and FLAIR MRIs confirm Cho/NAA abnormalities in the pre-RT sMRI scan, suggesting standard imaging underestimated the extent of tumor infiltration. (C) This patient had a large lesion of metabolically active tumor that was not shown in T1w-CE, thus, undertreated, which became apparent at recurrence.