VTR-297 (Trichostatin A) is a pan-inhibitor of histone deacetylases types 1, 2, 4, 6, and 10. Histone deacetylase inhibitors (HDACi) are well-known small molecules that increase the acetylation of lysine residues by inhibiting the activity of histone deacetylase enzymes. These anticancer agents affect epigenetic and non-epigenetic transcriptional regulation and are already part of effective clinical practice and hematology regimens. As HDACi are known for their relatively wide transcriptional modulation, we have conducted a high throughput screen to delineate early acetylation effects related to exposure to Trichostatin A (TSA) on patient-derived, clinical time-series samples.
NCT03838926 is an ongoing, open-label, dose-escalation, phase I clinical trial for subjects with relapsed or refractory hematologic malignancies. Enrolled patients were assigned to receive one currently tested dose (1.25 / 2.50 / 5.00 / 10 / 20mg; IV infusion) in 28-day cycles, 3-times a week for three weeks with one week off (IV administration days 1,3,5,8,10,12,15,17 and 19) until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was safety/tolerability and maximum tolerated dose (MTD) of VTR-297 (TSA).
Currently, eighteen patients enrolled in the study, including Acute Myeloid Leukemia (AML,n=1), Myelodysplastic Syndrome (MDS, n=1), Multiple Myeloma (MM, n=9), Non-Hodgkin's Lymphoma (NHL, n=5), and Hodgkin's Lymphoma (HL, n=2) across the first five dose-escalation cohorts that completed (1.25 / 2.50 / 5.00 / 10 / 20mg). No significant drug-related toxicities were reported during treatment, and MTD was not reached (recruitment is currently ongoing in the fifth dose cohort of 20mg).
As a part of the exploratory analysis of whole blood (PBMC), patient samples were collected on cycle1 day1 (C1D1; pre-infusion, 15min-post, 30min-post, 1h-post, 2h-post, and 6h-post infusion) to capture transcriptional activity related to VTR-297 treatment. In the current analysis, samples were collected and analyzed in respective batches and compared with baseline samples (pre-infusion). We selected genes that showed at least 1.5-fold expression difference and were statistically significant (p < 0.05). We identified 136 genes that were differentially expressed.
RNAseq data has shown enrichment of genes related to the core pathophysiology of myeloid and lymphoid disease (e.g., iron metabolism, vascular metastasis, and tyrosine kinase activity). We identified transcriptional profiles which suggest that TSA activity is already observed within first three dose cohorts and it might be partially mediated via modulation of well known, tyrosine kinases (FLT3, NTRK3) and others
Following this RNAseq work in the earlier doses studied, we examined the 10mg and 20mg cohorts with a Western Blot analysis that revealed the accumulation of acetylation signal in the treated samples when compared to pre-infusion samples. This is consistent with the hypothesis of potent VTR-297 HDACi activity.
In conclusion, these preliminary signatures offer early biomarker information related to a specific pattern of acetylation and transcriptional activity elicited by intravenously delivered VTR-297 in the clinical setting. In an ongoing clinical study, we will further monitor, validate, and expand on these findings. Further observations at higher, safe, and clinically meaningful doses will complement our current, early activity of VTR-297 and how it can be used to optimize patient treatments.
Przychodzen:Vanda Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.
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