Early Transcriptional Activity of Vtr-297 - Results from an Ongoing Phase I Clinical Trial

Abstract

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 elucidate early transcriptional 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 mg; 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, twelve patients enrolled in the study, including Multiple Myeloma (MM, n=5), Non-Hodgkin's Lymphoma (NHL, n=5), and Hodgkin's Lymphoma (HL, n=2) across the first three dose-escalation cohorts that completed (1.25 / 2.50 / 5.00mg). No significant drug-related toxicities were reported, and MTD was not reached (recruitment is currently ongoing in the fourth dose cohort of 10mg). 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 any transcriptional changes (RNAseq) related to VTR-297 treatment. In the current analysis, samples were collected and analyzed in respective batches (15min / 30min / 1h / 2h / 6h) and compared with combined baseline samples (pre-infusion). Using Deseq2 to ascertain transcriptionally affected genes (pval<0.05, up/down relative fold-change 1.5x), we detected 136 differentially expressed genes across at least one of the time point analyzed. Among the detected genes, we found novel and previously described genes related to the core pathophysiology of myeloid and lymphoid disease (e.g., iron metabolism, vascular metastasis, and tyrosine kinase activity). In conclusion, these preliminary signatures offer early biomarker information related to a specific 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 picture of VTR-297 activity and how it can be used to optimize TSA-based treatments.