Here, we report the final results of a pilot study adding belinostat to concurrent RT and TMZ for patients with newly diagnosed GBMs . Previously, the cohort receiving belinostat showed an improved 6-month PFS compared to the control cohort (54% vs. 84%, p = 0.073). A speculated reason for the improved PFS at 6 months but not at 12 months is that belinostat was only given to subjects for a short duration throughout RT. HDACis like belinostat are known to be reversible drugs, and, epigenetic stress in tumors and the microenvironment may resume in the absence of HDACi resulting in a truncated effect. In our final analysis, the median overall survival was promising appearing slightly longer (by about 2.7 months) for the belinostat cohort. While the result is not statistically significant, this may be in part due to the small sample size. In a recent cooperative group trial (NRG-BN001) comparing dose-escalated to conventional dose RT for newly diagnosed GBM patients, patients on the experimental arm that received dose-escalated photon radiation had a median OS of 18.7 months . The similarity in median OS benefit between the dose-escalated treatment arm of BN001 and our belinostat cohort points to the potential that belinostat may be a radiation sensitizer having a similar effect on patients comparable to dose escalation. In our trial, the voxel-based analysis of recurrence patterns comparing recurrent voxels to those in PTV2 indicates a potential shift of recurrences being more out-of-field suggesting that in-field control was improved due to the radiosensitizing effects of belinostat.
Pre-RT sMRI scans for a few representative belinostat patients reveal larger tumor extents (median volume difference was 6.2-folds between union of Cho/NAA ≥ 2x and residual tumor vs. residual tumor volume in all belinostat group patients) than were detected in standard imaging. Therefore, these portions of the lesion (as defined by Cho/NAA) were left undertreated. RT plans for all patients on the trial were guided by abnormality in T1w-CE and FLAIR only as per standard-of-care. Recurrence patterns confirm that pre-RT sMRI findings provide a possible reason for some in the belinostat cohort having an OS that was lower than that in historical controls.
The wide variability in OS suggests that some patients respond much more positively to a belinostat regimen while for others, the effect is minimal. While HDAC inhibitors are powerful epigenetic modulators, they are still target-specific drugs. They are hypothesized to work in the subgroup of patients whose tumorigenesis is driven by epigenetic modifications. This encourages investigation into whether certain subtypes of GBMs are more genetically predisposed to react positively to HDACi’s like belinostat. Unfortunately, our sample size was too small to identify molecular subtypes that were responsive to belinostat. Interestingly, one patient with an IDH mutation who responded remarkably well to belinostat . With this patient, there was not only a visible size reduction of metabolically active tumor volume but also the metabolic activity in the contralateral side of the brain was restored to healthy levels. This supports the observations reported by other groups that IDH1/2 mutations in GBM are associated with a fascinating link to 2-hydroxyglutarate (2-HG) accumulation representing an altered metabolite profile, which may have broad implications for both cancer epigenetics and clinical management of disease . While it is difficult to run a clinical trial in GBM with IDH mutation in a single institution since the incident rate is low, it may be beneficial to run a multisite trial to determine if GBM with IDH mutation are unusually sensitive to belinostat.
Patients receiving belinostat on our study appear to have a different recurrence pattern than those in the control cohort. In particular, the mean radiation dose to the rGTV region was statistically significantly lower in the belinostat cohort than that in the control cohort (51.5 Gy vs 62.0 Gy, p = 0.042) while other comparisons of the minimum and maximum dose to rGTV was similarly trending in the same direction. This suggests that concurrent belinostat may be delaying recurrences in regions that received higher radiation doses. The overlap between rGTV and PTV treatment zones was also lower in the belinostat cohort than that in the control cohort. Overall, these trends look promising for belinostat’s activity in GBM especially in concert with full dose RT. This is further supported by the three patients in the belinostat cohort that had out-of-field recurrence as the first site of recurrence. In them the belinostat was unable to significantly impede recurrences when RT dose was inadequate.
Finally, the addition of belinostat to concurrent RT/TMZ at a dose of 750 mg/m2/day x 5 days every 3 weeks starting 1 week prior to RT did result in DLTs in 2 of 3 patients that completed this therapy. In one case, grade 4 thrombocytopenia first developed just prior to cycle 1 of adjuvant TMZ. In the other case, grade 4 thrombocytopenia and neutropenia did not develop until after receiving 3 cycles of adjuvant TMZ (more than 4 months following the last treatment with belinostat). While it is possible that these were spurious events as these hematologic toxicities can occur with TMZ alone, the lack of hematologic DLTs in our control cohort (N = 13) and the remaining belinostat cohort (N = 10) treated at 500 mg/m2/day argues for implicating belinostat in these DLTs. Also, at the lower belinostat dose, no unusual toxicity was definitively noted. Thus, based on our limited experience, the dosing regimen of 3 cycles of belinostat at 500 mg/m2/day x 5 days every 3 weeks during concurrent RT/TMZ is well tolerated and should serve as a point of departure for dosing in future trials evaluating belinostat in combination with RT and TMZ.
In this trial, belinostat was only administered during RT. Since an HDACi such as belinostat is a reversible drug and epigenetic modification-induced stress remains, it is certainly possible that extended use of belinostat during the maintenance period after radiation therapy may further improve outcomes in patients. This will require future testing to assess the safety and efficacy of belinostat when combined with adjuvant TMZ.
In summary, we have established that belinostat can be safely given with concurrent RT and TMZ and is trending towards improving outcomes in newly-diagnosed GBM patients. Because recurrence volumes in the control cohort had larger overlap with PTV2s (volume receiving 60 Gy) than in the belinostat cohort, this suggests that belinostat has a better likelihood of delaying recurrence in those regions receiving 60 Gy. Trends in this study highlight the potential of belinostat, a BBB-penetrating HDACi, as a synergistic therapeutic agent for GBM treatment.