First-in-human study of 4SC-202, a novel oral HDAC inhibitor in advanced hematologic malignancies (TOPAS study).

8559 Background: 4SC-202 is a specific inhibitor of protein deacetylases HDAC1, 2 and 3 and lysine specific demethylase LSD1 (KDM1A). Enzymatic inhibition leads to transcriptional repression of Wnt and Hedgehog signaling. 4SC-202 provokes the inhibition of stemness-related properties of cancer cells and affects their viability. Methods: Patients with advanced hematological malignancies including AML, ALL, CLL, MM, MDS or lymphoma were orally dosed either once daily (QD) or twice daily (BID) from days 1 to 14, or BID continuously, in a 21-day cycle. Dose escalation followed a 3+3 design. Study objectives include safety, tolerability and pharmacokinetics (PK), determination of MTD and DLT as well as optimization of dosing. Biomarker program includes measuring of HDAC inhibition, total lysine acetylation and gene expression profiling. Additionally, the anti-tumor effect of 4SC-202 was evaluated. Dose escalation part is completed and data allow for reliable evaluation. Further patients will be enrolled to est...